4-(4-cyano-2-thioaryl)dihydropyrimidinones and their use

ABSTRACT

The present invention relates to novel 4-(4-cyano-2-thioaryl)dihydropyrimidin-2-one derivatives, to processes for their preparation, to their use alone or in combination for the treatment and/or prevention of diseases and also to their use for preparing medicaments for the treatment and/or prevention of diseases, in particular for the treatment and/or prevention of disorders of the lung and the cardiovascular system.

The present invention relates to novel4-(4-cyano-2-thioaryl)dihydropyrimidin-2-one derivatives, to processesfor their preparation, to their use alone or in combination for thetreatment and/or prevention of diseases and also to their use forpreparing medicaments for the treatment and/or prevention of diseases,in particular for the treatment and/or prevention of disorders of thelung and the cardiovascular system. Human leukocyte elastase (HLE, EC3.4.21.37), also called human neutrophil elastase (HNE, hNE), belongs tothe family of the serine proteases. The proteolytic enzyme is found inthe azurophilic granules of polymorphonuclear leukocytes (PMNleukocytes). Intracellular elastase performs an important function indefense against pathogens by breaking down the foreign particles takenby phagocytosis. Activated neutrophilic cells release the HNE from thegranules into the extracellular space (extracellular HNE), with some ofthe released HNE remaining on the outside of the neutrophilic cellmembrane (membrane-associated HNE). The highly active enzyme is able tobreak down a large number of connective tissue proteins, for example theproteins elastin, collagen and fibronectin. Elastin occurs in highconcentrations in all tissue types showing high elasticity, for examplein the lung and the arteries. HNE is involved in the tissue breakdownand transformation (tissue remodeling) associated with a large number ofpathological processes (for example tissue injuries). HNE is also animportant modulator of inflammatory processes. HNE induces for exampleincreased interleukin-8 (IL-8) gene expression.

Accordingly, it is presumed that HNE plays an important role in manydisorders, injuries and pathological changes whose formation and/orprogression are/is associated with inflammatory events and/orproliferative and hypertrophic tissue and vessel transformation. Thiscan be in particular disorders and/or injuries of the lung or thecardiovascular system, or it may be sepsis, cancerous disorders or otherinflammatory disorders.

Disorders and injuries of the lung which may be mentioned in thiscontext are in particular chronic obstructive pulmonary disease (COPD),acute respiratory distress syndrome (ARDS), cystic fibrosis (CF; alsoreferred to as mucoviscidosis), lung emphysema and acute lung injury(ALI). Disorders and injuries of the cardiovascular system where HNE isinvolved are, for example, tissue transformations during heart failureand reperfusion damage after acute myocardial infarction (AMI),cardiogenic shock, acute coronary syndrome (ACS), and also aneurysms.Disorders associated with sepsis are, for example, systemic inflammatoryresponse syndrome (SIRS), severe sepsis, septic shock and multi-organfailure (MOF; multi-organ dysfunction, MODS) and also disseminatedintravascular coagulation (DIC). Examples of tissue breakdown andtransformation in cancerous processes are the migration of cancer cellsinto healthy tissue (formation of metastases) and the formation of newsupply blood vessels (neo-angiogenesis). Other inflammatory diseaseswhere HNE plays a role are rheumatoid disorders, for example rheumatoidarthritis, inflammatory bowel disease (IBD), Crohn's disease (CD),ulcerative colitis (UC) and arteriosclerosis. It is generally assumedthat elastase-mediated pathological processes are based on a displaedequilibrium between free elastase and endogenous elastase inhibitorprotein (mainly alpha-1 antitrypsin, AAT) [Neutrophils andprotease/antiprotease imbalance, Stockley, Am. J. Respir. Grit. CareMed. 160, 49-52 (1999)]. AAT is present in large excess in the plasmaand thus very rapidly neutralizes free HNE. The concentration of freeelastase is elevated in various pathological processes, so that there isa local shift in the balance between protease and protease inhibitor infavor of the protease. In addition, membrane-associated elastase of theactivated PMN cells is very substantially protected from inhibition byAAT. The same applies to free elastase, which is located in amicrocompartment which is difficult to access between the neutrophiliccell and the adjoining tissue cell (for example endothelial cell). Inaddition, strong oxidizing conditions prevail in the vicinity ofactivated leukocytes (oxidative burst), and thus AAT is oxidized andloses several orders of magnitude in the inhibitory effect.

Novel elastase-inhibiting active compounds (exogenously administeredinhibitors of HNE) ought accordingly to have a low molecular weight inorder to be able also to reach and inhibit the membrane-associated HNEand the HNE present in the protected microcompartment (see above). Alsonecessary for this purpose is good in vivo stability of the substances(low in vivo clearance). In addition, these compounds ought to be stableunder oxidative conditions in order not to lose inhibitory power in thepathological process.

Pulmonary arterial hypertension (PAH) is a progressive lung disorderwhich, untreated, leads to death on average within 2.8 years after beingdiagnosed. An increasing constriction of the pulmonary circulation leadsto increased stress on the right heart, which may develop into rightheart failure. By definition, the main pulmonary aterial pressure (mPAP)in case of chronic pulmonary hypertension is >25 mmHg at rest or >30mmHg during exertion (normal value <20 mmHg). The pathophysiology ofpulmonary arterial hypertension is characterized by vasoconstriction andremodeling of the pulmonary vessels. In chronic PAH there isneomuscularization of initially unmuscularized pulmonary vessels, andthe vascular muscles of the already muscularized vessels increase incircumference. This increasing obliteration of the pulmonary circulationresults in progressive stress on the right heart, which leads to areduced output from the right heart and eventually ends in right heartfailure (M. Humbert et al., J. Am. Coll. Cardiol. 2004, 43, 13S-24S).PAH is an extremely rare disorder, with a prevalence of 1-2 per million.The average age of the patients has been estimated to be 36 years, andonly 10% of the patients were over 60 years of age. Distinctly morewomen than men are affected (G. E. D'Alonzo et al., Ann. Intern. Med.1991, 115, 343-349).

Despite all the advances in the therapy of pulmonary arterialhypertension there is as yet no prospect of cure of this seriousdisorder. Standard therapies available on the market (for exampleprostacyclin analogs, endothelin receptor antagonists, phosphodiesteraseinhibitors) are able to improve the quality of life, the exercisetolerance and the prognosis of the patients. The principles of thesetherapies are primarily hemodynamic, influencing vessel tone but havingno direct influence on the pathogenic remodeling processes. In addition,the possibility of using these medicaments is restricted through thesometimes serious side effects and/or complicated types ofadministration. The period over which the clinical situation of thepatients can be improved or stabilized by specific monotherapy islimited (for example owing to the development of tolerance). Eventuallythe therapy escalates and thus a combination therapy is applied, where aplurality of medicaments must be given concurrently.

Novel combination therapies are one of the most promising futuretherapeutic options for the treatment of pulmonary arterialhypertension. In this connection, the finding of novel pharmacologicalmechanisms for the treatment of PAH is of particular interest (Ghofraniet al., Herz 2005, 30, 296-302; E. B. Rosenzweig, Expert Opin. EmergingDrugs 2006, 11, 609-619; T. Ito et al., Curr. Med. Chem. 2007, 14,719-733). Therapeutic options which intervene directly in the remodelingevent (antiremodeling mechanisms) in particular might form the basis fora more causal treatment and thus be of great advantage for the patients.In this connection, it will be possible to combine known and noveltherapies. In order to minimize the risk of interferingmedicament-medicament interactions in such a combination therapy, thesenovel active compounds ought inhibit metabolizing P450 CYP enzymes onlyto a very small extent or not at all.

These days, one proceeds on the assumption that elastase plays a centralrole in pathological remodeling. It has been possible to find afragmentation of connective tissue (internal elastic lamina) in animalmodels and in patients with elevated pulmonary arterial blood pressure(pulmonary arterial hypertension) [Rabinovitch et al., Lab. Invest. 55,632-653 (1986)], and it was possible to show in animal models ofpulmonary arterial hypertension (hypoxic rat and mouse model,monocrotaline rat model) that elastase activity was increased and wasassociated with a fragmentation of connective tissue [Todorovich-Hunteret al., Am. Rev. Respir. Dis. 146, 213-223 (1992)]. It is suspected thatthe tissue remodeling to be observed during the disease process ofpulmonary arterial hypertension is induced by an elastase-mediatedrelease of connective tissue-associated growth factors, for example ofbasic fibroblast growth factor (bFGF) [Rabinovitch, Am. J. Physiol. 277,L5-L12 (1999)]. It was possible to show a positive effect with anoverexpressed elastase inhibitor protein in the hypoxic mouse model ofpulmonary arterial hypertension [Zaidi et al., Circulation 105, 516-521(2002)]. It was possible to show a positive effect with syntheticlow-molecular-weight elastase inhibitors in the monocrotaline rat modelof pulmonary arterial hypertension; in this case there was also abeneficial effect on tissue remodeling to be noted [Cowan et al., NatureMed. 6, 698-702 (2000)]. However, all previously disclosedlow-molecular-weight elastase inhibitors have low selectivity, arechemically reactive and/or have only limited oral availability, thus todate thwarting clinical development of an oral elastase inhibitor forthese indications. The term “pulmonary arterial hypertension” includesparticular types of pulmonary hypertension as have been specified forexample by the World Health Organization (WHO) (Clinical Classificationof Pulmonary Hypertension, Venedig 2003; G. Simonneau et al., J. Am.Coll. Cardiol. 2004, 43, 5S-12S). According to this classification,pulmonary arterial hypertension includes idiopathic pulmonary arterialhypertension (IPAH, formerly also called primary pulmonary hypertension,PPH), familial pulmonary arterial hypertension (FPAH), persistentpulmonary hypertension in neonates and also associated pulmonaryarterial hypertension (APAH) which is associated with collagenoses,congenital systemic-pulmonary shunt vitiae, portal hypertension, HIVinfections, intake of particular drugs and medicaments (for exampleanorectics), with disorders having a significant venous/capillaryinvolvement, such as pulmonary venal-occlusive disease and pulmonarycapillary hemangiomatosis, or with other disorders such as thyroiddisorders, glycogen storage diseases, Gaucher's disease, hereditaryteleangiectasia, hemoglobinopathies, myeloproliferative disorders andsplenectomy. Other types of pulmonary hypertension include, for example,the pulmonary hypertension associated with left heart disorders, forexample with ventricular or valvular disorders, the pulmonaryhypertension associated with disorders of the respiratory tract and/orof the lungs, for example with chronic obstructive lung disease,interstitial lung disease or pulmonary fibrosis, the pulmonaryhypertension attributable to chronic thrombotic and/or embolicdisorders, for example associated with thromboembolic obstruction ofpulmonary arteries, and the pulmonary hypertension caused by generallyinflammatory disease processes or by special causes (for exampleassociated with schistosomiasis, sarcoidosis, neoplastic diseases).

Chronic obstructive pulmonary disease (COPD) is a pulmonary diseasewhich progresses slowly and is characterized by obstruction of breathingcaused by pulmonary emphysema and/or chronic bronchitis. First symptomsof the disorder generally appear from the fourth to the fifth decade oflife onwards. In the years that follow, the short breath frequentlyworsens and cough, associated with extensive and sometimes prolongeddischarge and obstructed breathing up to breathlessness (dyspnea),manifests itself. COPD is primarily a smoker's disease: smoking isresponsible for 90% of all cases of COPD and 80-90% of all deaths causedby COPD. COPD is a major medical problem and represents the sixth mostfrequent cause of death world-wide. About 4-6% of people over the age of45 are affected. Although the obstruction of breathing may only bepartial and temporal, COPD cannot be cured. Accordingly, the target ofthe treatment is to improve the quality of life, to ameliorate thesymptoms, to prevent acute worsening and to slow the progressiveimpairment of pulmonary function. Existing pharmacotherapies, which havehardly changed over the last two to three decades, are the use ofbronchodilators to open up blocked respiratory paths, and in certainsituations corticosteroids to control the inflammation of the lung [P.J. Barnes, N. Engl. J. Med. 343, 269-280 (2000)]. The chronicinflammation of the lung, caused by cigarette smoke or other irritants,is the force behind the development of the disease. The mechanism onwhich it is based involves immune cells which, during the course of theinflammatory reaction of the lung, secrete various chemokines. Thisattracts neutrophilic cells and subsequently alveolar macrophages to theconnective tissue of the lung and the lumen. Neutrophilic cells secretea protease cocktail which contains mainly HNE and protease 3. Thiscauses the local protease/antiprotease balance to shift in favor of theproteases, resulting inter alia in an unchecked elastase activity and asa consequence thereof an excess degradation of the alveolar cells [J. E.Gadek et al., J. Clin. Invest. 68, 889-898 (1981); Z. Werb et al., J.Invest. Dermatol. 79, 154-159 (1982); A. Janoff, Am. Rev. Respir. Dis.132, 417-433 (1985); P. J. Barnes, N. Engl. J. Med. 343, 269-280(2000)]. This tissue degradation causes the bronchii to collapse. Thisis associated with a reduced elasticity of the lung, which leads toobstructed breathing and impaired respiration. In addition, frequent andpersistent inflammation of the lung may lead to remodeling of thebronchii and as a consequence to the formation of lesions. Such lesionscontribute to chronic cough, which characterizes chronic bronchitis.

Alpha-1 antitrypsin (AAT) is a small endogenous protein and represents,as mentioned above, the most important endogenous elastase inhibitor. Inpatients having a genetic deficiency of this protein (AADT), theprotease/antiprotease balance is shifted. Accordingly, in AADT patients,the effective radius and the duration of action of HNE is increased by afactor of 2.5 and 6.5, respectively [T. G. Liou and E. J. Campbell,Biochemistry 1995, 16171-16177]. AADT patients have an increased risk ofdeveloping pulmonary emphysema or COPD, and in many AADT patients a lungtransplant is indicated.

Acute lung injury (ALI) and the more pronounced form thereof, acuterespiratory distress syndrome (ARDS), are serious disorders associatedwith a mortality of 50-60%. According to the definition of the NorthAmerican-European Consensus Conference (NAECC) of 1994, ALI and ARDS aredefined by an acute onset, bilateral radiologically visible infiltrates,a PaO₂/FiO₂ index of ≦300 mmHg (ALI) or ≦200 mmHg (ARDS), a pulmonarycapillary wedge pressure of <18 mmHg and no clinical evidence of leftatrial hypertension.

The development of acute lung injury may be preceded both by pulmonaryand extrapulmonary disorders. Aspiration of stomach content, pneumonias,smoke poisoning, pulmonary contusion and near-drowning are considered tobe lung-specific predisposing factors. In particular the aspiration ofstomach content and pneumonias are frequently seen as initial disordersof ALI/ARDS of pulmonary origin. The most frequent indirect events arepolytrauma, sepsis, repeated blood transfusions, acute pancreatitis andburns. The incidence is 17.9 cases of ALI and 13.5 cases of ARDS per 100000 inhabitants and year [Luhr et al., Am. J. Respir. Grit. Care Med.159, 1849-1861 (1999)].

A central role in the development of these disorders is played by themassive inflammatory changes in the lung, which are triggered by awidely branched system of mediators. An important role in thedevelopment of lung injury is also played by neutrophilic granulocytes,the number of which increases permanently during the inflammatoryprocess [Chollet-Martin et al., Am. J. Respir. Grit. Care Med. 154,594-601 (1996)]. The action of the mediators causes damage to thealveolocapillary membranes, and this results in an increasedpermeability of the alveolar capillary barrier. Owing to the increasedpermeability, protein-rich fluid can permeate into the alveolae and alsointo the interstitial space; a low-pressure pulmonary edema develops.Characteristic for ALI/ARDS, this is a noncardiogenic edema. The edemafluid contains mainly fibrin, erythrocytes, leukocytes, hyalinemembranes and other proteins. Together with the products of activatedneutrophils, the protein-rich exudate leads to dysfunction of thesurfactant. The inflammatory processes cause damage and loss ofpneumocytes of type II, which form surfactant, resulting in a reducedsurfactant production. The surfactant deficit increases the surfacetension in the alveolae; the alveolae collapse and atelectases areformed. With perfusion being maintained, there is thus aventilation/perfusion imbalance resulting in an increase of thepulmonary right-left shunt. Furthermore, compliance is reduced, and incontrast the alveolar dead space is increased because there are areaswhich are ventilated but, owing to pulmonary hypertension, no longersufficiently perfused. An increased elastase activity, which correlatesto the severity of the lung injury, could be measured in thebronchoalveolar lavage fluid (BALF) of ARDS patients. In animal modelswhere the lung is injured (for example by administration of LPS), thiseffect can be reproduced. Here, treatment with elastase inhibitors (forexample sivelestat or elafin, vide infra,) reduces the elastase activityin the BALF considerably and improves lung function.

In Japan and South Korea, an elastase inhibitor (sivelestat, Elaspol) isapproved for the treatment of acute lung injury associated with SIRS.The reversible, but reactive compound has only a relatively weak effecton HNE (K_(i) 200 nM) and also acts on the pancreas elastase (IC₅₀ 5.6μM). The active compound is administered intravenously, oraladministration is not possible.

Elafin and structural analogs are also investigated as therapeuticallyuseful elastase inhibitors. Elafin is an endogenous small protein whichinhibits both elastase and proteinase 3. However, owing to theproteinergic character, oral administration of elafin is not possible.

WO 2004/024700, WO 2004/024701, WO 2005/082863 and WO 2005/082864disclose various 1,4-diaryldihydropyrimidin-2-one derivatives as HNEinhibitors for the treatment of chronic obstructive pulmonary disease,acute coronary syndrome, myocardial infarction and heart failure. Di-and multimers of such compounds for the treatment of respiratorydisorders are claimed in WO 2006/082412, WO 2006/136857 and WO2007/042815. 4-Aryldihydropyrimidin-2-one derivatives as inhibitors ofthe calcium channel function for the treatment of hypertension aredescribed in WO 2005/009392. WO 2007/129060 disclosestetrahydropyrrolopyrimidinediones and multimers thereof as HNEinhibitors. Meanwhile, WO 2008/003412 describes the use of1,4-diaryldihydropyrimidin-2-one derivatives for the treatment ofpulmonary arterial hypertension. It has now been found that1,4-diaryldihydropyrimidin-2-one derivatives are particularly suitablefor the treatment and/or prevention of disorders. These compoundsdescribed below are low-molecular-weight, non-reactive and selectiveinhibitors of human neutrophil elastase (HNE) which, surprisingly, showconsiderably better inhibition of this protease than the compounds knownfrom the prior art. In addition, the compounds according to theinvention have unexpectedly low in vitro clearance in hepatocytes andthus improved metabolic stability. Accordingly, these substances arepromising starting points for novel medicaments for the treatment and/orprevention of in particular disorders of the lung and the cardiovascularsystem.

Compared to the compounds of the prior art, the1,4-diaryldihydropyrimidin-2-one derivatives of the present inventionhave a structure which is distinguished by an ortho-sulfanyl,ortho-sulfinyl or ortho-sulfonyl substituent in the 4-aryl head group ofthe dihydropyrimidinone which, surprisingly, results in theabove-described improved properties of the compounds.

Specifically, the present invention relates to compounds of the generalformula (I)

in whichA and E both represent C—R⁷ or one of the two ring members A and Erepresents N and the other represents C—R⁷, in whichR⁷ represents in each case hydrogen, fluorine or chlorine,Z represents O or S,n represents the number 0, 1 or 2,R¹ represents (C₁-C₆)-alkyl which may be substituted by hydroxyl,(C₁-C₄)-alkoxy, amino, mono- or di-(C₁-C₄)-alkylamino, hydroxycarbonyl,aminocarbonyl, (C₃-C₆)-cycloalkyl, phenyl or 5- or 6-membered heteroarylor up to five times by fluorine, or represents (C₂-C₆)-alkenyl,(C₃-C₆)-cycloalkyl, phenyl or 5- or 6-membered heteroaryl,where the (C₃-C₆)-cycloalkyl groups mentioned may be substituted up totwo times by identical or different substituents from the groupconsisting of (C₁-C₄)-alkyl, hydroxyl and (C₁-C₄)-alkoxyandthe phenyl and heteroaryl groups mentioned may be substituted up to twotimes by identical or different substituents from the group consistingof fluorine, chlorine, cyano, (C₁-C₄)-alkyl, difluoromethyl,trifluoromethyl, (C₁-C₄)-alkoxy, difluoromethoxy and trifluoromethoxy,R² represents hydrogen, fluorine or chlorine,R³ represents cyano or a group of the formula —C(═O)—R⁸, —C(═O)—O—R⁸,—C(═O)—NH₂ or —C(═O)—NH—R⁸, in whichR⁸ represents (C₁-C₆)-alkyl, (C₃-C₆)-alkenyl or (C₃-C₆)-cycloalkyl,where (C₁-C₆)-alkyl and (C₃-C₆)-cycloalkyl for their part may besubstituted up to two times by identical or different substituents fromthe group consisting of hydroxyl, (C₁-C₄)-alkoxy, hydroxycarbonyl,(C₁-C₄)-alkoxycarbonyl, amino, mono- and di-(C₁-C₄)-alkylamino and in(C₁-C₆)-alkyl and (C₃-C₆)-cycloalkyl in each case one CH₂ group may bereplaced by an oxygen atom, if this results in a chemically stablecompound,R⁴ represents methyl or ethylorR³ and R⁴ are attached to one another and together form a fused group ofthe formula

in which* denotes the point of attachment to the 5-position, shown in formula(I), of the dihydropyrimidine ringand** denotes the point of attachment to the 6-position, shown in formula(I), of the dihydropyrimidine ringandR⁹ represents hydrogen, (C₁-C₆)-alkyl or (C₃-C₆)-cycloalkyl,where (C₁-C₆)-alkyl may be substituted by hydroxyl, (C₁-C₄)-alkoxy,aminocarbonyl, aminocarbonylamino, (C₁-C₄)-acylamino or(C₃-C₆)-cycloalkyl,R⁵ represents hydrogen or (C₁-C₆)-alkyl which may be substituted bycyano, hydroxyl, (C₁-C₄)-alkoxy, amino, mono- or di-(C₁-C₄)-alkylaminoor (C₃-C₆)-cycloalkyl or up to three times by fluorine, or representsphenyl, pyridyl or pyrimidinyl, where phenyl, pyridyl and pyrimidinylfor their part may be substituted up to two times by identical ordifferent substituents from the group consisting of fluorine, chlorine,cyano, (C₁-C₄)-alkyl, trifluoromethyl, (C₁-C₄)-alkoxy andtrifluoromethoxy,orR⁵ represents a group of the formula —C(═O)—O—R¹⁰, -L¹—C(═O)—O—R¹¹,-L²-C(═O)—NR¹²R¹³, -L²-SO₂—NR¹²R¹³, -L²-C(═O)—NR¹⁴—NR¹²R¹³ or-L²-SO₂—R¹⁵, in whichL¹ represents (C₁-C₆)-alkanediyl,L² represents a bond or (C₁-C₆)-alkanediyl,R¹⁰ represents (C₁-C₆)-alkyl which may be substituted by(C₃-C₆)-cycloalkyl or phenyl,R¹¹ represents hydrogen or (C₁-C₆)-alkyl which may be substituted by(C₃-C₆)-cycloalkyl or phenyl,R¹² and R¹³ are identical or different and independently of one anotherrepresent hydrogen, (C₁-C₆)-alkyl, (C₃-C₆)-cycloalkyl or 4- to6-membered heterocyclyl, where (C₁-C₆)-alkyl, (C₃-C₆)-cycloalkyl and 4-to 6-membered heterocyclyl for their part may be substituted up to twotimes by identical or different substituents from the group consistingof fluorine, hydroxyl, (C₁-C₄)-alkoxy, oxo, amino, mono- ordi-(C₁-C₄)-alkylamino, hydroxycarbonyl, (C₁-C₄)-alkoxycarbonyl andaminocarbonylandin (C₁-C₆)-alkyl a CH₂ group may be replaced by an oxygen atom, if thisresults in a chemically stable compound,and(C₃-C₆)-cycloalkyl and 4- to 6-membered heterocyclyl may additionally besubstituted up to two times by identical or different (C₁-C₄)-alkylradicals, which for their part may be substituted by hydroxyl,(C₁-C₄)-alkoxy or hydroxycarbonyl,orR¹² and R¹³ together with the nitrogen atom to which they are attachedform a 4- to 6-membered heterocycle which may contain a further ringheteroatom from the group consisting of N, O, S, SO and SO₂ and whichmay be substituted up to two times by identical or differentsubstituents from the group consisting of (C₁-C₄)-alkyl, hydroxyl,(C₁-C₄)-alkoxy, oxo, amino, mono- or di-(C₁-C₄)-alkylamino,hydroxycarbonyl, aminocarbonyl, (C₃-C₆)-cycloalkyl, 4- to 6-memberedheterocyclyl and 5- or 6-membered heteroaryl,where (C₁-C₄)-alkyl for its part may be substituted by hydroxyl,(C₁-C₄)-alkoxy or hydroxycarbonyl,R¹⁴ represents hydrogen or (C₁-C₄)-alkylandR¹⁵ represents (C₁-C₆)-alkyl, (C₃-C₆)-cycloalkyl, phenyl or 5- or6-membered heteroaryl,where (C₁-C₆)-alkyl may be substituted by chlorine, hydroxyl,(C₁-C₄)-alkoxy, mono- or di-(C₁-C₄)-alkylamino or (C₃-C₆)-cycloalkyl orup to three times by fluorineandphenyl and 5- or 6-membered heteroaryl for their part may be substitutedup to two times by identical or different substituents from the groupconsisting of fluorine, chlorine, cyano, (C₁-C₄)-alkyl, difluoromethyl,trifluoromethyl, (C₁-C₄)-alkoxy and trifluoromethoxy,andR⁶ represents hydrogen, fluorine or chlorine,and their salts, solvates and solvates of the salts.

Compounds according to the invention are the compounds of the formula(I) and the salts, solvates and solvates of the salts thereof, thecompounds of the formulae mentioned hereinafter and encompassed byformula (I) and the salts, solvates and solvates of the salts thereof,and the compounds which are mentioned hereinafter as exemplaryembodiments and encompressed by formula (I) and the salts, solvates andsolvates of the salts thereof, insofar as the compounds encompassed byformula (I) and mentioned hereinafter are not already salts, solvatesand solvates of the salts.

The compounds according to the invention may, depending on theirstructure, exist in various stereoisomeric forms, i.e. in the form ofconfigurational isomers or, if appropriate, also as conformationalisomers (enantiomers and/or diastereomers, including atropisomers). Thepresent invention therefore relates to the enantiomers and diastereomersand to their respective mixtures. The stereoisomerically pureconstituents can be isolated in a known manner from such mixtures ofenantiomers and/or diastereomers.

If the compounds according to the invention may occur in tautomericforms, the present invention encompasses all tautomeric forms.

Salts which are preferred for the purposes of the present invention arephysiologically acceptable salts of the compounds according to theinvention. Also encompassed are salts which are themselves unsuitablefor pharmaceutical uses but can be used for example for isolating orpurifying the compounds according to the invention.

Physiologically acceptable salts of the compounds according to theinvention include acid addition salts of mineral acids, carboxylic acidsand sulfonic acids, for example salts of hydrochloric acid, hydrobromicacid, sulfuric acid, phosphoric acid, methanesulfonic acid,ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid,naphthalenedisulfonic acid, acetic acid, trifluoroacetic acid, propionicacid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid,maleic acid and benzoic acid. Physiologically acceptable salts of thecompounds according to the invention also include salts of conventionalbases such as, by way of example and preferably, alkali metal salts (forexample sodium salts and potassium salts), alkaline earth metal salts(for example calcium salts and magnesium salts) and ammonium saltsderived from ammonia or organic amines having 1 to 16 carbon atoms, suchas, by way of example and preferably, ethylamine, diethylamine,triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine,triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine,dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine andN-methylpiperidine.

Solvates refers for the purposes of the invention to those forms of thecompounds according to the invention which form, in the solid or liquidstate, a complex by coordination with solvent molecules. Hydrates are aspecific form of solvates in which the coordination takes place withwater. Hydrates are preferred solvates in the context of the presentinvention.

The present invention additionally encompasses prodrugs of the compoundsof the invention. The term “prodrugs” encompasses compounds whichthemselves may be biologically active or inactive, but are convertedduring their residence time in the body into compounds according to theinvention (for example by metabolism or hydrolysis).

In the context of the present invention, the substituents have thefollowing meaning, unless specified otherwise:

(C₁-C₆)-Alkyl and (C₁-C₄)-alkyl stand for the purposes of the inventionfor a straight-chain or branched alkyl radical having respectively 1 to6 and 1 to 4 carbon atoms. A straight-chain or branched alkyl radicalhaving 1 to 4 carbon atoms is preferred. Examples which may bepreferably mentioned are: methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, 1-ethylpropyl, n-pentyl, neopentyl andn-hexyl. (C₁-C₆)-Alkanediyl stands for the purpose of the invention fora straight-chain or branched divalent alkyl radical having 1 to 6 carbonatoms. A straight-chain or branched alkanediyl radical having 1 to 4carbon atoms is preferred. Examples which may be preferably mentionedare: methylene, ethane-1,2-diyl (1,2-ethylene), ethane-1,1-diyl,propane-1,3-diyl (1,3-propylene), propane-1,1-diyl, propane-1,2-diyl,propane-2,2-diyl, butane-1,4-diyl(1,4-butylene), butane-1,2-diyl,butane-1,3-diyl, butane-2,3-diyl, pentane-1,5-diyl(1,5-pentylene),pentane-2,4-diyl, 3-methylpentane-2,4-diyl andhexane-1,6-diyl(1,6-hexylene).

(C₂-C₆)-Alkenyl and (C₃-C₆)-alkenyl stand for the purposes of theinvention for a straight-chain or branched alkenyl radical havingrespectively 2 to 6 and 3 to 6 carbon atoms and one or two double bonds.A straight-chain or branched alkenyl radical having 3 to 6 carbon atomsand one double bond is preferred. Examples which may be preferablymentioned are: allyl, isopropenyl, n-but-2-en-1-yl, n-but-3-en-1-yl,n-pent-2-en-1-yl, n-pent-3-en-1-yl, n-pent-4-en-1-yl,3-methylbut-2-en-1-yl and 4-methylpent-3-en-1-yl.

(C₁-C₄)-Alkoxy stands for the purposes of the invention for astraight-chain or branched alkoxy radical having 1 to 4 carbon atoms.Examples which may be preferably mentioned are: methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy and tert-butoxy.

(C₁-C₄)-Alkoxycarbonyl stands for the purposes of the invention for astraight-chain or branched alkoxy radical having 1 to 4 carbon atomswhich is attached via a carbonyl group. Examples which may be preferablymentioned are: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl,isopropoxycarbonyl, n-butoxycarbonyl and tert-butoxycarbonyl.

Mono-(C₁-C₄)-alkylamino stands for the purposes of the invention for anamino group having a straight-chain or branched alkyl substituent whichhas 1 to 4 carbon atoms. Examples which may be preferably mentioned are:methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino andtert-butylamino.

Di-(C₁-C₄)-alkylamino stands for the purposes of the invention for anamino group having two identical or different straight-chain or branchedalkyl substituents having in each case 1 to 4 carbon atoms. Exampleswhich may be preferably mentioned are: N,N-dimethylamino,N,N-diethylamino, N-ethyl-N-methylamino, N-methyl-N-n-propylamino,N-isopropyl-N-methylamino, N-isopropyl-N-n-propylamino,N,N-diisopropylamino, N-n-butyl-N-methylamino andN-tert-butyl-N-methylamino.

(C₁-C₄)-Acyl [(C₁-C₄)-alkanoyl] stands for the purposes of the inventionfor a straight-chain or branched alkyl radical having 1 to 4 carbonatoms which has a doubly attached oxygen atom in the 1-position and isattached via the 1-position. Examples which may be preferably mentionedare: formyl, acetyl, propionyl, n-butyryl and isobutyryl.

(C₁-C₄)-Acylamino stands for the purposes of the invention for an aminogroup having a straight-chain or branched acyl substituent which has 1to 4 carbon atoms and is attached via the carbonyl group to the nitrogenatom. Examples which may be preferably mentioned are: formylamino,acetylamino, propionylamino, n-butyrylamino and isobutyrylamino.

(C₃-C₆)-Cycloalkyl stands for the purposes of the invention for amonocyclic saturated cycloalkyl group having 3 to 6 ring carbon atoms.Examples which may be preferably mentioned are: cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl. 4- to 6-membered heterocyclyl stands for thepurposes of the invention for a monocyclic saturated heterocycle havinga total of 4 to 6 ring atoms which contains one or two ring heteroatomsfrom the group consisting of N, O, S, SO and SO₂ and is attached via aring carbon atom or, if appropriate, a ring nitrogen atom. Preference isgiven to a 5- or 6-membered heterocycle having one or two ringheteroatoms from the group consisting of N, O and S. Examples which maybe mentioned are: azetidinyl, oxetanyl, pyrrolidinyl, pyrazolidinyl,tetrahydrofuranyl, thiolanyl, piperidinyl, piperazinyl,tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl andthiomorpholinyl. Preference is given to pyrrolidinyl, tetrahydrofuranyl,piperidinyl, piperazinyl, tetrahydropyranyl and morpholinyl.

5- or 6-membered heteroaryl stands for the purposes of the invention foran aromatic heterocycle (heteroaromatic) having a total of 5 or 6 ringatoms which contains one or two ring heteroatoms from the groupconsisting of N, O and S and is attached via a ring carbon atom or, ifappropriate, a ring nitrogen atom. Examples which may be mentioned are:furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl,isoxazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyridazinyl andpyrazinyl. Preference is given to thienyl, thiazolyl, pyridyl,pyrimidinyl, pyridazinyl and pyrazinyl.

When radicals in the compounds according to the invention aresubstituted, the radicals may be mono- or polysubstituted, unlessspecified otherwise. For the purposes of the present invention, themeanings of all radicals which occur more than once are independent ofone another. Preference is given to substitution by one or two identicalor different substituents. Very particularly preferred is substitutionby one substituent.

In a particular embodiment, the present invention embraces compounds ofthe formula (I) in which

A and E both represent C—R⁷ or one of the two ring members A and Erepresents N and the other represents C—R⁷, in whichR⁷ represents in each case hydrogen, fluorine or chlorine,Z represents O or S,n represents the number 0, 1 or 2,R¹ represents (C₁-C₆)-alkyl which may be substituted by hydroxyl,(C₁-C₄)-alkoxy, amino, mono- or di-(C₁-C₄)-alkylamino, hydroxycarbonyl,aminocarbonyl, (C₃-C₆)-cycloalkyl or phenyl, or represents(C₂-C₆)-alkenyl, (C₃-C₆)-cycloalkyl or phenyl, where the(C₃-C₆)-cycloalkyl groups mentioned may be substituted up to two timesby identical or different substituents from the group consisting of(C₁-C₄)-alkyl, hydroxyl and (C₁-C₄)-alkoxyandthe phenyl groups mentioned may be substituted up to two times byidentical or different substituents from the group consisting offluorine, chlorine, cyano, (C₁-C₄)-alkyl, difluoromethyl,trifluoromethyl, (C₁-C₄)-alkoxy, difluoromethoxy and trifluoromethoxy,R² represents hydrogen, fluorine or chlorine,R³ represents cyano or a group of the formula —C(═O)—R⁸, —C(═O)—O—R⁸,—C(═O)—NH₂ or —C(═O)—NH—R⁸, in whichR⁸ represents (C₁-C₆)-alkyl, (C₃-C₆)-alkenyl or (C₃-C₆)-cycloalkyl,where (C₁-C₆)-alkyl and (C₃-C₆)-cycloalkyl for their part may besubstituted up to two times by identical or different substituents fromthe group consisting of hydroxyl, (C₁-C₄)-alkoxy, hydroxycarbonyl,(C₁-C₄)-alkoxycarbonyl, amino, mono- and di-(C₁-C₄)-alkylamino and in(C₁-C₆)-alkyl and (C₃-C₆)-cycloalkyl in each case one CH₂ group may bereplaced by an oxygen atom, if this results in a chemically stablecompound,R⁴ represents methyl or ethylorR³ and R⁴ are attached to one another and together form a fused group ofthe formula

in which* denotes the point of attachment to the 5-position, shown in formula(I), of the dihydropyrimidine ring and** denotes the point of attachment to the 6-position, shown in formula(I), of the dihydropyrimidine ringandR⁹ represents hydrogen, (C₁-C₆)-alkyl or (C₃-C₆)-cycloalkyl,where (C₁-C₆)-alkyl may be substituted by hydroxyl, (C₁-C₄)-alkoxy,aminocarbonyl, (C₁-C₄)-acylamino or (C₃-C₆)-cycloalkyl,R⁵ represents hydrogen or (C₁-C₆)-alkyl which may be substituted up tothree times by fluorine, or represents phenyl, pyridyl or pyrimidinyl,where phenyl, pyridyl and pyrimidinyl for their part may be substitutedup to two times by identical or different substituents from the groupconsisting of fluorine, chlorine, cyano, (C₁-C₄)-alkyl, trifluoromethyl,(C₁-C₄)-alkoxy and trifluoromethoxy,orR⁵ represents a group of the formula —C(═O)—O—R¹⁰, -L¹—C(═O)—O—R¹¹,-L²-C(═O)—NR¹²R¹³, -L²-SO₂—NR¹²R¹³, -L²-C(═O)—NR¹⁴—NR¹²R¹³ or-L²-SO₂—R¹⁵, in whichL¹ represents (C₁-C₆)-alkanediyl,L² represents a bond or (C₁-C₆)-alkanediyl,R¹⁰ represents (C₁-C₆)-alkyl,R¹¹ represents hydrogen or (C₁-C₆)-alkyl,R¹² and R¹³ are identical or different and independently of one anotherrepresent hydrogen, (C₁-C₆)-alkyl, (C₃-C₆)-cycloalkyl or 4- to6-membered heterocyclyl, where (C₁-C₆)-alkyl, (C₃-C₆)-cycloalkyl and 4-to 6-membered heterocyclyl for their part may be substituted up to twotimes by identical or different substituents from the group consistingof fluorine, hydroxyl, (C₁-C₄)-alkoxy, oxo, amino, mono- ordi-(C₁-C₄)-alkylamino, hydroxycarbonyl, (C₁-C₄)-alkoxycarbonyl andaminocarbonyl and in (C₁-C₆)-alkyl a CH₂ group may be replaced by anoxygen atom, if this results in a chemically stable compound,orR¹² and R¹³ together with the nitrogen atom to which they are attachedform a 4- to 6-membered heterocycle which may contain a further ringheteroatom from the group consisting of N, O, S, SO and SO₂ and may besubstituted up to two times by identical or different substituents fromthe group consisting of (C₁-C₄)-alkyl, hydroxyl, (C₁-C₄)-alkoxy, oxo,amino, mono- and di-(C₁-C₄)-alkylamino, where (C₁-C₄)-alkyl for its partmay be substituted by hydroxyl or (C₁-C₄)-alkoxy,R¹⁴ represents hydrogen or (C₁-C₄)-alkylandR¹⁵ represents (C₁-C₆)-alkyl, (C₃-C₆)-cycloalkyl, phenyl or 5- or6-membered heteroaryl,where (C₁-C₆)-alkyl may be substituted by fluorine, chlorine, hydroxyl,(C₁-C₄)-alkoxy, mono- or di-(C₁-C₄)-alkylaminoandphenyl and 5- or 6-membered heteroaryl for their part may be substitutedup to two times by identical or different substituents from the groupconsisting of fluorine, chlorine, cyano, (C₁-C₄)-alkyl, trifluoromethyl,(C₁-C₄)-alkoxy and trifluoromethoxy,andR⁶ represents hydrogen, fluorine or chlorine, and their salts, solvatesand solvates of the salts.

Preferred for the purposes of the present invention are compounds of theformula (I)

in whichA and E both represent CHandR² represents hydrogen, and their salts, solvates and solvates of thesalts.

Preference is likewise given to compounds of the formula (I) in which

Z represents O,and to their salts, solvates and solvates of the salts.

Particularly preferred for the purposes of the present invention arecompounds of the formula (I) in which

A and E both represent CH,Z represents O,n represents the number 0 or 2,R¹ represents (C₁-C₄)-alkyl which may be substituted by hydroxyl,(C₁-C₄)-alkoxy, hydroxycarbonyl, aminocarbonyl, (C₃-C₆)-cycloalkyl,phenyl or 5-membered heteroaryl or up to three times by fluorine, orrepresents (C₃-C₆)-cycloalkyl, phenyl or 5-membered heteroaryl,where the phenyl and heteroaryl groups mentioned may be substituted upto two times by identical or different substituents from the groupconsisting of fluorine, chlorine, cyano, methyl, trifluoromethyl,methoxy and trifluoromethoxy,R² represents hydrogen,R³ represents cyano, acetyl or (2-hydroxyethoxy)carbonyl,R⁴ represents methylorR³ and R⁴ are attached to one another and together form a fused group ofthe formula

in which* denotes the point of attachment to the 5-position, shown in formula(I), of the dihydropyrimidine ringand** denotes the point of attachment to the 6-position, shown in formula(I), of the dihydropyrimidine ringandR⁹ represents hydrogen, (C₁-C₄)-alkyl or (C₃-C₆)-cycloalkyl, where(C₁-C₄)-alkyl may be substituted by hydroxyl or (C₁-C₄)-alkoxy,R⁵ represents hydrogen or (C₁-C₄)-alkyl which may be substituted bycyano or di-(C₁-C₄)-alkylamino, or represents a group of the formula-L²-C(═O)—NR¹²R¹³, -L²-C(═O)—NH—NR¹²R¹³ or -L²-SO₂—R¹⁵, in whichL² represents a bond, —CH₂—, —CH₂CH₂— or —CH(CH₃)—,R¹² represents hydrogen or (C₁-C₄)-alkyl which may be substituted byhydroxyl or (C₁-C₄)-alkoxy,R¹³ represents hydrogen, (C₁-C₆)-alkyl or (C₃-C₆)-cycloalkyl, where(C₁-C₆)-alkyl may be substituted up to two times by identical ordifferent substituents from the group consisting of hydroxyl,(C₁-C₄)-alkoxy, hydroxycarbonyl, (C₁-C₄)-alkoxycarbonyl andaminocarbonyl and in (C₁-C₆)-alkyl a CH₂ group may be replaced by anoxygen atom, if this results in a chemically stable compound, orR¹² and R¹³ together with the nitrogen atom to which they are attachedform a 5- or 6-membered heterocycle which may contain a further ringheteroatom from the group consisting of N, O and S and may besubstituted by (C₁-C₄)-alkyl, hydroxyl, (C₁-C₄)-alkoxy, oxo,hydroxycarbonyl, aminocarbonyl, 4- to 6-membered heterocyclyl or 5- or6-membered heteroaryl,

where (C₁-C₄)-alkyl for its part may be substituted by hydroxyl,(C₁-C₄)-alkoxy or hydroxycarbonyl,

andR¹⁵ represents (C₁-C₄)-alkyl, (C₃-C₆)-cycloalkyl or phenyl, where(C₁-C₄)-alkyl may be substituted by (C₃-C₆)-cycloalkylandphenyl may be substituted up to two times by identical or differentsubstituents from the group consisting of fluorine, chlorine, cyano,methyl, trifluoromethyl, methoxy and trifluoromethoxy,andR⁶ represents hydrogen or fluorine,and their salts, solvates and solvates of the salts.

In a further particularly preferred embodiment, the present inventionembraces compounds of the formula (I) in which

A and E both represent CH,Z represents O,n represents the number 0 or 2,R¹ represents (C₁-C₄)-alkyl which may be substituted by hydroxyl,(C₁-C₄)-alkoxy, hydroxycarbonyl, aminocarbonyl, (C₃-C₆)-cycloalkyl orphenyl, or represents (C₃-C₆)-cycloalkyl or phenyl,where the phenyl groups mentioned may be substituted up to two times byidentical or different substituents from the group consisting offluorine, chlorine, cyano, methyl, trifluoromethyl, methoxy andtrifluoromethoxy,R² represents hydrogen,R³ represents cyano or acetyl,R⁴ represents methylorR³ and R⁴ are attached to one another and together form a fused group ofthe formula

in which* denotes the point of attachment to the 5-position, shown in formula(I), of the dihydropyrimidine ringand** denotes the point of attachment to the 6-position, shown in theformula (I), of the dihydropyrimidine ringandR⁹ represents hydrogen, (C₁-C₄)-alkyl or (C₃-C₆)-cycloalkyl,where (C₁-C₄)-alkyl may be substituted by hydroxyl or (C₁-C₄)-alkoxy,R⁵ represents hydrogen, (C₁-C₄)-alkyl or a group of the formula-L²-C(═O)—NR¹²R¹³, -L²-C(═O)—NH—NR¹²R¹³ or -L²-SO₂—R¹⁵, in whichL² represents a bond, —CH₂—, —CH₂CH₂— or —CH(CH₃)—,R¹² represents hydrogen or (C₁-C₄)-alkyl which may be substituted byhydroxyl or (C₁-C₄)-alkoxy,R¹³ represents hydrogen, (C₁-C₆)-alkyl or (C₃-C₆)-cycloalkyl,where (C₁-C₆)-alkyl may be substituted up to two times by identical ordifferent substituents from the group consisting of hydroxyl,(C₁-C₄)-alkoxy, hydroxycarbonyl, (C₁-C₄)-alkoxycarbonyl andaminocarbonyl and in (C₁-C₆)-alkyl a CH₂ group may be replaced by anoxygen atom, if this results in a chemically stable compound,orR¹² and R¹³ together with the nitrogen atom to which they are attachedform a 5- or 6-membered heterocycle which may contain a further ringheteroatom from the group consisting of N, O and S and may besubstituted by (C₁-C₄)-alkyl, hydroxyl, (C₁-C₄)-alkoxy or oxo,where (C₁-C₄)-alkyl for its part may be substituted by hydroxyl or(C₁-C₄)-alkoxy,andR¹⁵ represents (C₁-C₄)-alkyl, (C₃-C₆)-cycloalkyl or phenyl,where phenyl may be substituted up to two times by identical ordifferent substituents from the group consisting of fluorine, chlorine,cyano, methyl, trifluoromethyl, methoxy and trifluoromethoxy,andR⁶ represents hydrogen or fluorine,and their salts, solvates and solvates of the salts.

Especially preferred for the purposes of the present invention arecompounds of the formula (I) in which

A and E both represent CH,Z represents O,n represents the number 2,R¹ represents (C₁-C₄)-alkyl which may be substituted by hydroxyl,(C₁-C₄)-alkoxy, cyclopropyl, cyclobutyl or phenyl or up to three timesby fluorine,R² represents hydrogen,R³ represents cyano or (2-hydroxyethoxy)carbonyl,R⁴ represents methyl,R⁵ represents hydrogen, (C₁-C₄)-alkyl or a group of the formula-L²-C(═O)—NH—R¹³ or —SO₂—R¹⁵, in whichL² represents a bond or —CH₂—,R¹³ represents hydrogen or (C₁-C₄)-alkyl which may be substituted byhydroxyl or (C₁-C₄)-alkoxy, or (C₃-C₆)-cycloalkyl andR¹⁵ represents (C₁-C₄)-alkyl or (C₃-C₆)-cycloalkyl,andR⁶ represents hydrogen,and their salts, solvates and solvates of the salts.

Very particularly preferred for the purposes of the present inventionare compounds of the formula (I) in which

A and E both represent CH,Z represents O,n represents the number 2,R¹ represents (C₁-C₄)-alkyl which may be substituted by hydroxyl or(C₁-C₄)-alkoxy,R² represents hydrogen,R³ represents cyano,R⁴ represents methyl,R⁵ represents hydrogen, (C₁-C₄)-alkyl or a group of the formula—CH₂-0(═O)—NH—R¹³ or —SO₂—R¹⁵, in whichR¹³ represents hydrogen or (C₁-C₄)-alkyl which may be substituted byhydroxyl or (C₁-C₄)-alkoxyandR¹⁵ represents (C₁-C₄)-alkyl or (C₃-C₆)-cycloalkyl,andR⁶ represents hydrogen,and their salts, solvates and solvates of the salt.

Of particular relevance are compounds according to formula (I) havingthe configuration shown in formula (I-ent) at the 4-position of thedihydropyrimidine ring

in which A, E, Z, n, R¹, R², R³, R⁴, R⁵ and R⁶ each have the meaningsgiven above, and their salts, solvates and solvates of the salts.

Specific radical definitions given in the respective combinations orpreferred combinations of radicals are, independently of thecombinations of radicals given in each case, also replaced by anyradical definitions of other combinations.

Very particular preference is given to combinations of two or more ofthe preferred ranges mentioned above.

The invention furthermore provides a process for preparing the compoundsof the formula (I) according to the invention, characterized in that acompound of the formula (II)

in which A, E, n, R¹ and R² each have the meanings given above, isreacted in the presence of an acid or an acid anhydride in a 3-componentone-pot reaction or sequentially with a compound of the formula (III)

in which R³ and R⁴ have the meanings given above, and a compound of theformula (IV)

in which Z and R⁶ have the meanings given above, is reacted to give acompound of the formula (I-A)

in which A, E, Z, n, R¹, R², R³, R⁴ and R⁶ each have the meanings givenabove, and this compound is, in the case that R⁵ in formula (I) does notrepresent hydrogen, reacted in the presence of a base with a compound ofthe formula (V)

R^(5A)—X  (V),

in whichR^(5A) has the meaning of R⁵ given above, but does not representhydrogen, andX represents a leaving group, such as, for example, halogen, mesylate,tosylate or triflate,to give a compound of the formula (I-B)

in which A, E, Z, n, R¹, R², R³, R⁴, R^(5A) and R⁶ each have themeanings given above, and the compound of the formula (I-A) or (I-B)obtained in this manner is, if appropriate, separated by methods knownto the person skilled in the art into its enantiomers and/ordiastereomers and/or converted with the appropriate (i) solvents and/or(ii) bases or acids into its solvates, salts and/or solvates of thesalts. Suitable solvents for the process step (II)+(III)+(IV)→(I-A) areusual organic solvents which are not altered under the reactionconditions. These include, for example, ethers, such as diethyl ether,diisopropyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxaneor tetrahydrofuran, alcohols, such as methanol, ethanol, n-propanol,isopropanol, n-butanol or tert-butanol, hydrocarbons, such as pentane,hexane, cyclohexane, benzene, toluene or xylene, halogenatedhydrocarbons, such as dichloromethane, 1,2-dichloroethane,trichloromethane or chlorobenzene, or other solvents, such as ethylacetate, acetonitrile, dimethyl sulfoxide or N,N-dimethylformamide. Itis also possible to use mixtures of the solvents mentioned. Preferenceis given to using methyl tert-butyl ether, tetrahydrofuran or dioxane.Suitable as acid for the process step (II)+(III)+(IV)→(I-A) are usualinorganic or organic acids or acid anhydrides. These include preferablycarboxylic acids, such as, for example, acetic acid or trifluoroaceticacid, sulfonic acids, such as methanesulfonic acid,trifluoromethanesulfonic acid or p-toluenesulfonic acid, hydrochloricacid, sulfuric acid, phosphoric acid, phosphonic acids, or phosphoric orphosphonic anhydrides or esters, such as polyphosphoric acid, phosphoricacid triethyl ester, polyphosphoric acid ethyl ester, phosphoruspentoxide or propanephosphonic anhydride. Preference is given to usingphosphoric acid triethyl ester in combination with phosphorus pentoxide.The acid is generally employed in an amount of from 0.25 mol to 100 molbased on 1 mol of the compound (III). Process step (II)+(III)+(IV)→(I-A)is generally carried out in a temperature range from +20° C. to +150°C., preferably at +50° C. to +100° C. The reaction can be carried outunder atmospheric, elevated or reduced pressure (for example from 0.5 to5 bar). It is generally carried out under atmospheric pressure.

Solvents suitable for process step (I-A)+(V)→(I-B) are usual organicsolvents which are not altered under the reaction conditions. Theseinclude, for example, ethers, such as diethyl ether, diisopropyl ether,methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane ortetrahydrofuran, hydrocarbons, such as pentane, hexane, cyclohexane,benzene, toluene or xylene, halogenated hydrocarbons, such asdichloromethane, 1,2-dichloroethane, trichloromethane or chlorobenzene,or other solvents, such as ethyl acetate, acetone, methyl ethyl ketone,methyl tert-butyl ketone, acetonitrile, dimethyl sulfoxide,N,N-dimethylformamide, N,N′-dimethylpropyleneurea (DMPU) orN-methylpyrrolidone (NMP). It is also possible to use mixtures of thesolvents mentioned. Preference is given to using tetrahydrofuran,acetonitrile or dimethylformamide.

Suitable as base for the process step (I-A)+(V)→(I-B) are usualinorganic or organic bases. These include in particular alkali metal oralkaline earth metal carbonates, such as lithium carbonate, sodiumcarbonate, potassium carbonate, calcium carbonate or cesium carbonate,alkali metal alkoxides, such as sodium tert-butoxide or potassiumtert-butoxide, alkali metal hydrides, such as sodium hydride orpotassium hydride, amides, such as lithium bis(trimethylsilyl)amide orpotassium bis(trimethylsilyl)amide or lithium diisopropylamide (LDA),organic amines, such as triethylamine, N-methylmorpholine,N-methylpiperidine, N,N-diisopropylethylamine,1,5-diazabicyclo[4.3.0]non-5-ene (DBN),1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), pyridine or4-N,N-dimethylaminopyridine, or phosphazine bases (“Schwesinger bases”),such as, for example, P1-t-Bu, P2-t-Bu or P4-t-Bu. Preference is givento using potassium carbonate, cesium carbonate, sodium hydride,triethylamine, N,N-diisopropylethylamine or lithiumbis(trimethylsilyl)amide; sodium hydride and lithiumbis(trimethylsilyl)amide are particularly preferred. The base isgenerally employed in an amount of from 0.1 mol to 10 mol, preferablyfrom 1 mol to 3 mol, based on 1 mol of the compound (I-A).

Process step (I-A)+(V)→(I-B) is generally carried out in a temperaturerange from −78° C. to +100° C., preferably at −78° C. to +80° C.,particularly preferably at −78° C. to +25° C. The reaction can becarried out under atmospheric, elevated or reduced pressure (for examplefrom 0.5 to 5 bar). It is generally carried out under atmosphericpressure.

Compounds according to the invention of the formula (I) in which R³ andR⁴ are attached to one another, and, together, form a fused group of theformula

in which * and ** are the points of attachment described above and R⁹has the meaning given abovecan also be prepared by brominating a compound of the formula (I-C)

in which A, E, Z, n, R¹, R² and R⁶ each have the meanings given aboveandR^(8A) represents (C₁-C₆)-alkyl, (C₃-C₆)-alkenyl or (C₃-C₆)-cycloalkyl,in an inert solvent to give a compound of the formula (VI)

in which A, E, Z, n, R¹, R², R⁶ and R^(8A) each have the meanings givenaboveand then cyclizing it with a compound of the formula (VII)

R⁹—NH₂  (VII)

in which R⁹ has the meaning given above to give a compound of theformula (I-D)

in which A, E, Z, n, R¹, R², R⁶ and R⁹ each have the meanings givenabove, which is subsequently, if appropriate, converted with a compoundof the formula (V), as described above, into a compound of the formula(I-E)

in which A, E, Z, n, R¹, R², R^(5A), R⁶ and R⁹ each have the meaningsgiven above.

The bromination in process step (I-C)→(VI) is preferably carried outusing elemental bromine in a usual inert solvent, such as chloroform, ata temperature from −20° C. to +40° C. A CC double bond, which mayoptionally be present in the radical R^(8A)[R^(8A)═(C₃-C₆)-alkenyl], mayalso be brominated under these reaction conditions; however, this doesnot interfere with the subsequent ring-closure reaction with thecompound (VII).

The lactam formation in process step (VI)+(VII)→(I-D) is preferablycarried out in an ether such as tetrahydrofuran or dioxane as inertsolvent at a temperature from −20° C. to +60° C. If appropriate, it maybe advantageous to use a tertiary amine, such as triethylamine,N-methylmorpholine, N-methylpiperidine or N,N-diisopropylethylamine asauxiliary base.

For its part, the compound of the formula (I-C) can be obtainedaccording to the reaction (II)+(III)+(IV)→(I-A) described above. Ifexpedient, further compounds of the formula (I) according to theinvention can also be prepared by transformations of functional groupsof individual substituents, in particular those listed under R¹, R³ andR⁵, starting with other compounds of the formula (I) obtained by theabove process. These transformations are carried out according tocustomary methods known to the person skilled in the art and include,for example, reactions such as nucleophilic or electrophilicsubstitution reactions, transition metal-mediated coupling reactions(for example Suzuki or Heck reaction), oxidation, reduction,hydrogenation, alkylation, acylation, amination, hydroxylation,etherification, esterification, ester cleavage and ester hydrolysis,formation of nitriles, carboxamides, sulfonamides, carbamates and ureas,and also the introduction and removal of temporary protective groups[cf. also the reaction schemes 2-5 below and the exemplary embodiments].

Separation of the compounds according to the invention into thecorresponding enantiomers and/or diastereomers is possible, asexpedient, at the stage of the compounds (I-B) or (I-E) or else at thestage of the compounds (I-A), (I-C) or (I-D), where the latter can then,in separated form, be reacted further according to the process stepsdescribed above. Such a separation of stereoisomers can be carried outby customary methods known to the person skilled in the art; preferenceis given to chromatographic methods, in particular to HPLCchromatography on a chiral phase.

The compounds of the formulae (III), (IV), (V) and (VII) arecommercially available, known per se from the literature or can beprepared by customary methods described in the literature.

Some of the compounds of the formula (II) are known from the literature,or they can be prepared analogously to processes described in theliterature [cf. also reaction schemes 6-9 below and the literature citedtherein].

In the process described above, it may, if appropriate, be syntheticallyexpedient to employ, instead of the compound of the formula (II),initially a compound of the formula (II-A)

in which A, E and R² have the meanings given above andY represents an exchangeable group, such as, for example, fluorine,chlorine, bromine, iodine, nitro or amino,in the reaction sequence described and then to introduce the ortho-thiosubstituent R¹—S(O)_(n)— of the aryl head group at the stage of thedihydropyrimidinone—which corresponds to the compound (I-A) or (I-B)—inexchange for the radical Y [cf. reaction scheme 10 below]. Some of thecompounds of the formula (II-A) are likewise known from the literature,or they can be prepared analogously to methods known from theliterature.

The processes described above can be illustrated by the reaction schemesbelow:

[cf., for example, W. K. Fife, J. Org. Chem. 48, 1375 (1983); H.Vorbruggen and K. Krolikiewicz, Synthesis, 316 (1983); R. T. Shuman etal., J. Org. Chem. 55, 738 (1990); C. S. Burgey et al., J. Med. Chem. 46(4), 461 (2003); V. M. Naidan et al., J. Gen. Chem. USSR (Engl. Transl.)55 (2), 346 (1985)].

[cf., for example, W. K. Fife, J. Org. Chem. 48, 1375 (1983); H.Vorbruggen and K. Krolikiewicz, Synthesis, 316 (1983); R. T. Shuman etal., J. Org. Chem. 55, 738 (1990); C. S. Burgey et al., J. Med. Chem. 46(4), 461 (2003); J. J. Li et al., J. Med. Chem. 39, 1846 (1996); K. N.Dack et al., Bioorg. Med. Chem. Lett. 8 (16), 2061 (1998)].

The compounds according to the invention have useful pharmacologicalproperties and can be used for prevention and treatment of disorders inhumans and animals. The compounds according to the invention arelow-molecular-weight, unreactive and selective inhibitors of humanneutrophil elastase which, surprisingly, show a considerably morepronounced inhibition of this protease than the compounds known from theprior art. In addition, the compounds according to the inventionunexpectedly have lower in vitro clearance by hepatocytes and thusimproved metabolic stability.

Accordingly, the compounds according to the invention are particularlysuitable for the treatment and/or prevention of disorders andpathological processes, in particular those where neutrophil elastase(HNE) is involved in an inflammatory event and/or a tissue or vesselremodeling.

For the purposes of the present invention, this includes in particulardisorders such as pulmonary arterial hypertension (PAH) and other formsof pulmonary hypertension (PH), chronic obstructive pulmonary disease(COPD), acute respiratory distress syndrome (ARDS), acute lung injury(ALI), alpha-1-antitrypsin deficiency (AATD), pulmonary fibrosis,pulmonary emphysema, cystic fibrosis, acute coronary syndrome (ACS),inflammations of the heart muscle (myocarditis) and other autoimmuneheart disorders (pericarditis, endocarditis, valvolitis, aortitis,cardiomyopathies), myocardial infarction, cardiogenic shock, heartfailure, aneurysms, sepsis (SIRS), multi-organ failure (MODS, MOF),arteriosclerosis, inflammatory disorders of the kidney, chronicinflammations of the intestine (IBD, CD, UC), pancreatitis, peritonitis,rheumatoid disorders, inflammatory skin disorders and also inflammatoryeye disorders.

The compounds according to the invention can furthermore be used for thetreatment and/or prevention of asthmatic disorders of various severitywith intermittent or persistent progression (refractive asthma,bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma,asthma induced by medicaments or by dust), of multifarious forms ofbronchitis (chronic bronchitis, infectious bronchitis, eosinophilicbronchitis), of bronchiolitis obliterans, bronchiectasia, pneumonia,farmer's lung and related diseases, cough and cold diseases (chronicinflammatory cough, iatrogenic cough), inflammations of the nasal mucosa(including medicament-induced rhinitis, vasomotoric rhinitis andseasonal allergic rhinitis, for example hayfever) and of polyps.

In addition, the compounds according to the invention can also be usedfor the treatment and/or prevention of micro- and macrovascular injuries(vasculitis), reperfusion damage, arterial and venous thromboses,diabetic and non-diabetic nephropathy, glomerulonephritis,glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis,microalbuminuria, acute and chronic renal insufficiency, acute andchronic renal failure, cystitis, urethritis, prostatitis, epidymititis,oophoritis, salpingitis, vulvovaginitis, erectile dysfunction, Hunner'saltsa, Peyronie's disease, arterial hypertension, shock, atrial andventricular arrhythmias, transitory and ischemic attacks, heart failure,stroke, endothelial dysfunction, peripheral and cardiovasculardisorders, impaired peripheral perfusion, edema formation such as, forexample, pulmonary edema, brain edema, renal edema and heartfailure-related edema, restenoses, for example after thrombolysistherapies, percutaneous transluminal angioplasties (PTA), transluminalcoronary angioplasties (PTCA), heart transplants and bypass operations,for increased levels of fibrinogen and low-density LDL and also forincreased concentrations of plasminogen activator inhibitor 1 (PAI-1),of dyslipidemias (hypercholesterolemia, hypertriglyceridemia, increasedconcentrations of postprandial plasma triglycerides,hypoalpha-lipoproteinemia, combined hyperlipidemias) and also metabolicdisorders (metabolic syndrome, hyperglycemia, insulin-dependentdiabetes, non-insulin-dependent diabetes, gestational diabetes,hyperinsulinemia, insulin resistance, glucose intolerance, adipositasand diabetic sequelae, such as retinopathy, nephropathy and neuropathy),neoplastic disorders (skin cancer, brain tumors, breast cancer, bonemarrow tumors, leukemias, liposarcomas, carcinomas of thegastrointestinal tract, the liver, the pancreas, the lungs, the kidneys,the urethra, the prostate and the genital tract and also malignanttumors of the lymphoproliferative system, such as, for example,Hodgkin's and non-Hodgkin's lymphoma), of disorders of thegastrointestinal tract and the abdomen (glossitis, gingivitis,periodontitis, esophagitis, eosinophilic gastroenteritis, mastocytosis,Crohn's disease, colitis, proctitis, pruritis ani, diarrhea, celiacdisease, hepatitis, hepatic fibrosis, cirrhosis of the liver,pancreatitis and cholecystitis), of disorders of the central nervoussystem and neurodegenerative disorders (stroke, Alzheimer's disease,Parkinson's disease, dementia, epilepsy, depressions, multiplesclerosis), immune disorders, thyroid disorders (hyperthyreosis), skindisorders (psoriasis, acne, eczema, neurodermitis, multifarious forms ofdermatitis, such as, for example, dermatitis abacribus, dermatitisactinica, dermatitis allergica, dermatitis ammoniacalis, dermatitisartefacta, dermatitis autogenica, dermatitis atrophicans, dermatitiscalorica, dermatitis combustionis, dermatitis congelationis, dermatitiscosmetica, dermatitis escharotica, dermatitis exfoliativa, dermatitisgangraenose, dermatitis haemostatica, dermatitis herpetiformis,dermatitis lichenoides, dermatitis linearis, dermatitis maligna,dermatitis medimencatosa, dermatitis palmaris et plantaris, dermatitisparasitaria, dermatitis photoallergica, dermatitis phototoxica,dermatitis pustularis, dermatitis seborrhoica, dermatitis solaris,dematitis toxica, dermatitis ulcerosa, dermatitis veneata, infectiousdermatitis, pyogenic dermatitis and rosacea-like dermatitis, and alsokeratitis, bullosis, vasculitis, cellulitis, panniculitis, lupuserythematosus, erythema, lymphomas, skin cancer, Sweet syndrome,Weber-Christian syndrome, scar formation, wart formation, chilblains),of inflammatory eye diseases (saccoidosis, blepharitis, conjunctivitis,iritis, uveitis, chorioiditis, ophthalmitis), viral diseases (caused byinfluenza, adeno and corona viruses, such as, for example, HPV, HCMV,HIV, SARS), of disorders of the skeletal bone and the joints and alsothe skeletal muscle (multifarious forms of arthritis, such as, forexample, arthritis alcaptonurica, arthritis ankylosans, arthritisdysenterica, arthritis exsudativa, arthritis fungosa, arthritisgonorrhoica, arthritis mutilans, arthritis psoriatica, arthritispurulenta, arthritis rheumatica, arthritis serosa, arthritissyphilitica, arthritis tuberculosa, arthritis urica, arthritisvillonodularis pigmentosa, atypical arthritis, hemophilic arthritis,juvenile chronic arthritis, rheumatoid arthritis and metastaticarthritis, furthermore Still syndrome, Felty syndrome, Sjörgen syndrome,Glutton syndrome, Poncet syndrome, Pott syndrome and Reiter syndrome,multifarious forms of arthropathias, such as, for example, arthropathiedeformans, arthropathie neuropathica, arthropathie ovaripriva,arthropathie psoriatica and arthropathie tabica, systemic scleroses,multifarious forms of inflammatory myopathies, such as, for example,myopathie epidemica, myopathie fibrosa, myopathie myoglobinurica,myopathie ossificans, myopathie ossificans neurotica, myopathieossificans progressiva multiplex, myopathie purulenta, myopathierheumatica, myopathie trichinosa, myopathie tropica and myopathietyphosa, and also the Günther syndrome and the Münchmeyer syndrome), ofinflammatory changes of the arteries (multifarious forms of arteritis,such as, for example, endarteritis, mesarteritis, periarteritis,panarteritis, arteritis rheumatica, arteritis deformans, arteritistemporalis, arteritis cranialis, arteritis gigantocellularis andarteritis granulomatosa, and also Horton syndrome, Churg-Strausssyndrome and Takayasu arteritis), Muckle-Well syndrome, Kikuchi disease,of polychondritis, dermatosclerosis and also other disorders having aninflammatory or immunological component, such as, for example, cataract,cachexia, osteoporosis, gout, incontinence, lepra, Sezary syndrome andparaneoplastic syndrome, for rejection reactions after organ transplantsand for wound healing and angiogenesis in particular in the case ofchronic wounds.

By virtue of their property profile, the compounds according to theinvention are suitable in particular for the treatment and/or preventionof pulmonary arterial hypertension (PAH) and other forms of pulmonaryhypertension (PH), chronic obstructive lung disease (COPD), acute lunginjury (ALI), acute respiratory distress syndrome (ARDS), pulmonaryemphysema, alpha-1-antitrypsin deficiency (AATD), cystic fibrosis (CF),sepsis and systemic-inflammatory response syndrome (SIRS), multipleorgan failure (MOF, MODS), inflammatory intestinal disorders (IBD,Crohn's disease, colitis), chronic bronchitis, bronchiolitis, asthma,rhinitis, rheumatoid arthritis, inflammatory skin and eye diseases,arteriosclerosis and neoplastic disorders.

The present invention furthermore provides the use of the compoundsaccording to the invention for the treatment and/or prevention ofdisorders, in particular the disorders mentioned above.

The present invention furthermore provides the use of the compoundsaccording to the invention for preparing a medicament for the treatmentand/or prevention of disorders, in particular the disorders mentionedabove.

The present invention furthermore provides the use of the compoundsaccording to the invention in a method for the treatment and/orprevention of disorders, in particular the disorders mentioned above.

The present invention furthermore provides a method for the treatmentand/or prevention of disorders, in particular the disorders mentionedabove, using an effective amount of at least one of the compoundsaccording to the invention.

The compounds according to the invention can be employed alone or, ifrequired, in combination with other active compounds. Accordingly, thepresent invention furthermore provides medicaments comprising at leastone of the compounds according to the invention and one or more furtheractive compounds, in particular for the treatment and/or prevention ofthe disorders mentioned above. Suitable active compounds forcombinations are, by way of example and preferably: compounds whichinhibit the signal transduction cascade, for example and preferably fromthe group of the kinase inhibitors, in particular from the group of thetyrosine kinase and/or serine/threonine kinase inhibitors; compoundswhich inhibit the degradation and remodeling of the extracellularmatrix, by way of example and preferably inhibitors of matrixmetalloproteases (MMPs), in particular inhibitors of stromelysin,collagenases, gelatinases and aggrecanases (here in particular of MMP-1,MMP-3, MMP-8, MMP-9, MMP-10, MMP-11 and MMP-13) and of metalloelastase(MMP-12); organic nitrates and NO donors, such as, for example, sodiumnitroprusside, nitroglycerin, isosorbide mononitrate, isosorbidedinitrate, molsidomine or SIN-1, and also inhaled NO;

NO-independent but hem-dependent stimulators of soluble guanylatecyclase, such as, in particular, the compounds described in WO 00/06568,WO 00/06569, WO 02/42301 and WO 03/095451;NO- and hem-independent activators of soluble guanylate cyclase, suchas, in particular, the compounds described in WO 01/19355, WO 01/19776,WO 01/19778, WO 01/19780, WO 02/070462 and WO 02/070510;prostacycline analogs, such as, by way of example and preferably,iloprost, beraprost, treprostinil or epoprostenol;compounds which inhibit soluble epoxide hydrolase (sEH), such as, forexample, N,N′-dicyclohexylurea, 12-(3-adamantan-1-ylureido)dodecanoicacid or 1-adamantan-1-yl-3-{5-[2-(2-ethoxyethoxy)ethoxy]pentyl}urea;compounds which influence the energy metabolism of the heart, such as,by way of example and preferably, etomoxir, dichloroacetate, ranolazineor trimetazidine; compounds which inhibit the degradation of cyclicguanosine monophosphate (cGMP) and/or cyclic adenosine monophosphate(cAMP), such as, for example, inhibitors of phosphodiesterases (PDE) 1,2, 3, 4 and/or 5, in particular PDE 5 inhibitors, such as sildenafil,vardenafil and tadalafil; agents having antithrombotic action, by way ofexample and preferably from the group of the platelet aggregationinhibitors, of anticoagulants or of profibrinolytic substances;active compounds which lower blood pressure, by way of example andpreferably from the group of the calcium antagonists, angiotensin Allantagonists, ACE inhibitors, vasopeptidase inhibitors, endothelinantagonists, renin inhibitors, alpha-receptor blockers, beta-receptorblockers, mineralocorticoid receptor antagonists, Rho kinase inhibitorsand diuretics;agents having a bronchodilatory effect, by way of example and preferablyfrom the group of the beta-adrenergic receptor agonists, such as, inparticular, albuterol, isoproterenol, metaproterenol, terbutalin,formoterol or salmeterol, or from the group of the anticholinergics,such as, in particular, ipratropium bromide; agents havingantiinflammatory action, by way of example and preferably from the groupof the glucocorticoids, such as, in particular, prednisone,prednisolone, methylprednisolone, triamcinolone, dexamethasone,beclomethasone, betamethasone, flunisolide, budesonide or futicasone;and/or active ingredients which alter lipid metabolism, for example andpreferably from the group of the thyroid receptor agonists, cholesterolsynthesis inhibitors, such as, by way of example and preferably, HMG-CoAreductase inhibitors or squalene synthesis inhibitors, of ACATinhibitors, CETP inhibitors, MTP inhibitors, PPAR-alpha, PPAR-gammaand/or PPAR-delta agonists, cholesterol absorption inhibitors, lipaseinhibitors, polymeric bile adsorbents, bile acid reabsorption inhibitorsand lipoprotein(a) antagonists.

In a preferred embodiment of the invention, the compounds according tothe invention are employed in combination with a kinase inhibitor suchas by way of example and preferably bortezomib, canertinib, erlotinib,gefitinib, imatinib, lapatinib, lestaurtinib, lonafarnib, pegaptinib,pelitinib, semaxanib, sorafenib, sunitinib, tandutinib, tipifarnib,vatalanib, fasudil, lonidamine, leflunomide, BMS-3354825 or Y-27632.

Agents having an antithrombotic effect preferably mean compounds fromthe group of platelet aggregation inhibitors, of anticoagulants or ofprofibrinolytic substances. In a preferred embodiment of the invention,the compounds according to the invention are administered in combinationwith a platelet aggregation inhibitor such as by way of example andpreferably aspirin, clopidogrel, ticlopidine or dipyridamole. In apreferred embodiment of the invention, the compounds according to theinvention are administered in combination with a thrombin inhibitor suchas by way of example and preferably ximelagatran, melagatran,bivalirudin or clexane. In a preferred embodiment of the invention, thecompounds according to the invention are administered in combinationwith a GPIIb/IIIa antagonist such as by way of example and preferablytirofiban or abciximab.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a factor Xa inhibitorsuch as by way of example and preferably rivaroxaban, DU-176b,fidexaban, razaxaban, fondaparinux, idraparinux, PMD-3112, YM-150,KFA-1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803,SSR-126512 or SSR-128428.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with heparin or a lowmolecular weight (LMW) heparin derivative.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a vitamin Kantagonist such as by way of example and preferably coumarin.

Agents which lower blood pressure preferably mean compounds from thegroup of calcium antagonists, angiotensin All antagonists, ACEinhibitors, endothelin antagonists, renin inhibitors, alpha-receptorblockers, beta-receptor blockers, mineralocorticoid receptorantagonists, Rho kinase inhibitors, and diuretics.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a calcium antagonistsuch as by way of example and preferably nifedipine, amlodipine,verapamil or diltiazem.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an alpha-1 receptorblocker such as by way of example and preferably prazosin.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a beta-receptorblocker such as by way of example and preferably propranolol, atenolol,timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol,metipranolol, nadolol, mepindolol, carazalol, sotalol, metoprolol,betaxolol, celiprolol, bisoprolol, carteolol, esmolol, labetalol,carvedilol, adaprolol, landiolol, nebivolol, epanolol or bucindolol.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an angiotensin Allantagonist such as by way of example and preferably losartan,candesartan, valsartan, telmisartan or embusartan.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an ACE inhibitor suchas by way of example and preferably enalapril, captopril, lisinopril,ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an endothelinantagonist such as by way of example and preferably bosentan,darusentan, ambrisentan or sitaxsentan.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a renin inhibitorsuch as by way of example and preferably aliskiren, SPP-600 or SPP-800.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a mineralocorticoidreceptor antagonist such as by way of example and preferablyspironolactone or eplerenone.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a Rho kinaseinhibitor such as by way of example and preferably fasudil, Y-27632,SLx-2119, BF-66851, BF-66852, BF-66853, KI-23095, SB-772077, GSK-269962Aor BA-1049.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a diuretic such as byway of example and preferably furosemide.

Agents which alter lipid metabolism preferably mean compounds from thegroup of CETP inhibitors, thyroid receptor agonists, cholesterolsynthesis inhibitors such as HMG-CoA reductase inhibitors or squalenesynthesis inhibitors, of ACAT inhibitors, MTP inhibitors, PPAR-alpha,PPAR-gamma and/or PPAR-delta agonists, cholesterol absorptioninhibitors, polymeric bile acid adsorbents, bile acid reabsorptioninhibitors, lipase inhibitors and lipoprotein(a) antagonists.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a CETP inhibitor suchas by way of example and preferably torcetrapib (CP-529 414), JJT-705 orCETP vaccine (Avant).

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a thyroid receptoragonist such as by way of example and preferably D-thyroxine,3,5,3′-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214).

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an HMG-CoA reductaseinhibitor from the class of statins such as by way of example andpreferably lovastatin, simvastatin, pravastatin, fluvastatin,atorvastatin, rosuvastatin, cerivastatin or pitavastatin.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a squalene synthesisinhibitor such as by way of example and preferably BMS-188494 orTAK-475.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an ACAT inhibitorsuch as by way of example and preferably avasimibe, melinamide,pactimibe, eflucimibe or SMP-797.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an MTP inhibitor suchas by way of example and preferably implitapide, BMS-201038, R-103757 orJTT-130.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a PPAR-gamma agonistsuch as by way of example and preferably pioglitazone or rosiglitazone.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a PPAR-delta agonistsuch as by way of example and preferably GW-501516 or BAY 68-5042.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a cholesterolabsorption inhibitor such as by way of example and preferably ezetimibe,tiqueside or pamaqueside.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a lipase inhibitorsuch as by way of example and preferably orlistat.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a polymeric bile acidadsorbent such as by way of example and preferably cholestyramine,colestipol, colesolvam, CholestaGel or colestimide.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a bile acidreabsorption inhibitor such as by way of example and preferablyASBT(=IBAT) inhibitors such as, for example, AZD-7806, S-8921, AK-105,BARI-1741, SC-435 or SC-635.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a lipoprotein(a)antagonist such as by way of example and preferably gemcabene calcium(CI-1027) or nicotinic acid. The present invention further providesmedicaments comprising at least one compound according to the invention,usually in combination with one or more inert, non-toxic,pharmaceutically suitable excipients, and their use for the purposesmentioned above.

The compounds according to the invention may have systemic and/or localeffects. For this purpose, they can be administered in a suitable waysuch as, for example, by the oral, parenteral, pulmonary, nasal,sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctivalor otic route or as implant or stent.

The compounds according to the invention can be administered inadministration forms suitable for these administration routes.

Suitable for oral administration are administration forms which functionaccording to the prior art and deliver the compounds according to theinvention rapidly and/or in a modified manner, and which contain thecompounds of the invention in crystalline and/or amorphized and/ordissolved form, such as, for example, tablets (uncoated and coatedtablets, for example having coatings which are resistant to gastricjuice or are insoluble or dissolve with a delay and control the releaseof the compound of the invention), tablets which disintegrate rapidly inthe mouth, or films/wafers, films/lyophilizates, capsules (for examplehard or soft gelatin capsules), sugar-coated tablets, granules, pellets,powders, emulsions, suspensions, aerosols or solutions.

Parenteral administration can take place with avoidance of an absorptionstep (e.g. intravenous, intraarterial, intracardiac, intraspinal orintralumbar) or with inclusion of an absorption (e.g inhalative,intramuscular, subcutaneous, intracutaneous, percutaneous, orintraperitoneal). Administration forms suitable for parenteraladministration are, inter alia, preparations for injection and infusionin the form of solutions, suspensions, emulsions, lyophilizates orsterile powders.

Suitable for the other routes of administration are, for example,pharmaceutical forms for inhalation (inter alia powder inhalers,nebulizers, aerosols), nasal drops, solutions, sprays; tablets forlingual, sublingual or buccal administration, films/wafers or capsules,suppositories, preparations for the ears and eyes, vaginal capsules,aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions,ointments, creams, transdermal therapeutic systems (for examplepatches), milk, pastes, foams, dusting powders, implants or stents.

Oral or parenteral administration are preferred, especially oral andintravenous administration and administration by inhalation.

The compounds according to the invention can be converted into thestated administration forms. This can take place in a manner known perse by mixing with inert, non-toxic, pharmaceutically suitableexcipients. These excipients include inter alia carriers (for examplemicrocrystalline cellulose, lactose, mannitol), solvents (e.g. liquidpolyethylene glycols), emulsifiers and dispersants or wetting agents(for example sodium dodecyl sulfate, polyoxysorbitan oleate), binders(for example polyvinylpyrrolidone), synthetic and natural polymers (forexample albumin), stabilizers (e.g. antioxidants such as, for example,ascorbic acid), colorings (e.g. inorganic pigments such as, for example,iron oxides) and masking flavors and/or odors.

It has generally proved to be advantageous on parenteral administrationto administer amounts of about 0.001 to 1 mg/kg, preferably about 0.01to 0.5 mg/kg of body weight per day to achieve effective results. Onoral administration, the dosage is about 0.01 to 100 mg/kg, preferablyabout 0.01 to 20 mg/kg, and very particularly preferably about 0.1 to 10mg/kg of body weight.

It may nevertheless be necessary where appropriate to deviate from thestated amounts, in particular as a function of body weight,administration route, individual response to the active ingredient, typeof preparation and time or interval over which administration takesplace. Thus, in some cases it may be sufficient to make do with lessthan the aforementioned minimum amount, whereas in other cases the upperlimit mentioned must be exceeded. Where relatively large amounts areadministered, it may be advisable to distribute these in a plurality ofsingle doses over the day. The following exemplary embodimentsillustrate the invention. The invention is not restricted to theexamples.

The percentage data in the following tests and examples are, unlessindicated otherwise, percentages by weight; parts are parts by weight.Solvent ratios, dilution ratios and concentration data of liquid/liquidsolutions are based in each case on the volume.

A. EXAMPLES Abbreviations

aq. aqueous, aqueous solution c concentration cat. catalytic CDIN,N′-carbonyldiimidazole TLC thin-layer chromatography DCI directchemical ionization (in MS) dist. distilled DIEAN,N-diisopropylethylamine DMAP 4-N,N-dimethylaminopyridine DMFdimethylformamide DMSO dimethyl sulfoxide ee enantiomeric excess entenantiomerically pure enantiomer eq. equivalent(s) ESI electrosprayionization (in MS) Et ethyl GC-MS gas chromatography-coupled massspectrometry h hour(s) HATUO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-hexafluorophosphate HPLC high-pressure, high-performance liquidchromatography conc. concentrated LC-MS liquid chromatography-coupledmass spectrometry MCPBA meta-chloroperbenzoic acid Me methyl minminute(s) MPLC medium-pressure liquid chromatography MS massspectrometry MTBE methyl tert-butyl ether NMR nuclear magnetic resonancespectrometry Ph phenyl PyBOPbenzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphatequant. quantitative (in yield) rac racemic, racemate RT room temperatureR_(t) retention time (in HPLC) m.p. melting point tBu tert-butyl TFAtrifluoroacetic acid TFAA trifluoroacetic anhydride THF tetrahydrofuranUV ultraviolet spectrometry v/v volume to volume ratio (of a solution)HPLC, GC-MS and LC-MS methods:

Method 1 (GC-MS):

Instrument: Micromass GCT, GC 6890; column: Restek RTX-35, 15 m×200μm×0.33 μm; constant helium flow: 0.88 ml/min; oven: 70° C.; inlet: 250°C.; gradient: 70° C., 30° C./min→310° C. (maintained for 3 min).

Method 2 (Analytical HPLC):

Instrument: HP 1100 with DAD detection; column: Kromasil 100 RP-18, 60mm×2.1 mm, 3.5 μm; mobile phase A: 5 ml of HClO₄ (70% strength)/liter ofwater, mobile phase B: acetonitrile; gradient: 0 min 2% B→0.5 min 2%B→4.5 min 90% B→9.0 min 90% B→9.2 min 2% B→10 min 2% B; flow rate: 0.75ml/min; column temperature: 30° C.; UV detection: 210 nm.

Method 3 (Analytical HPLC):

Instrument: HP 1100 with DAD detection; column: Kromasil 100 RP-18, 60mm×2.1 mm, 3.5 μm; mobile phase A: 5 ml of HClO₄ (70% strength)/liter ofwater, mobile phase B: acetonitrile; gradient: 0 min 2% B→0.5 min 2%B→4.5 min 90% B→6.5 min 90% B→6.7 min 2% B→7.5 min 2% B; flow rate: 0.75ml/min; column temperature: 30° C.; UV detection: 210 nm.

Method 4 (LC-MS):

Instrument: Micromass QuattroPremier with Waters HPLC Acquity; column:Thermo Hypersil GOLD 1.9μ 50 mm×1 mm; mobile phase A: 1 l of water+0.5ml of 50% strength formic acid, mobile phase B: 1 l of acetonitrile+0.5ml of 50% strength formic acid; gradient: 0.0 min 90% A→0.1 min 90%A→1.5 min 10% A→2.2 min 10% A; flow rate: 0.33 ml/min; oven: 50° C.; UVdetection: 210 nm.

Method 5 (LC-MS):

MS instrument type: Micromass ZQ; HPLC instrument type: Waters Alliance2795; column: Phenomenex Synergi 2.5p MAX-RP 100A Mercury 20 mm×4 mm;mobile phase A: 1 l of water+0.5 ml of 50% strength formic acid, mobilephase B: 1 l of acetonitrile+0.5 ml of 50% strength formic acid;gradient: 0.0 min 90% A→0.1 min 90% A→3.0 min 5% A→4.0 min 5% A→4.01 min90% A; flow rate: 2 ml/min;

oven: 50° C.; UV detection: 210 nm.

Method 6 (LC-MS):

MS instrument type: Micromass ZQ; HPLC instrument type: HP 1100 Series;UV DAD; column: Phenomenex Gemini 3p 30 mm×3.0 mm; mobile phase A: 1 lof water+0.5 ml of 50% strength formic acid, mobile phase B: 1 l ofacetonitrile+0.5 ml of 50% strength formic acid; gradient: 0.0 min 90%A→2.5 min 30% A→3.0 min 5% A→4.5 min 5% A; flow rate: 0.0 min 1ml/min→2.5 min/3.0 min/4.5 min 2 ml/min; oven: 50° C.; UV detection: 210nm.

Method 7 (Preparative HPLC/MS):

MS instrument: Waters ZQ 2000; HPLC instrument: Agilent 1100, 2-columnsystem; autosampler: HTC PAL; column: YMC-ODS-AQ, 50 mm×4.6 mm, 3.0 μm;mobile phase A: water+0.1% formic acid, mobile phase B:acetonitrile+0.1% formic acid; gadient: 0.0 min 100% A→0.2 min 95% A→1.8min 25% A→1.9 min 10% A→2.0 min 5% A→3.2 min 5% A→3.21 min 100% A→3.35min 100% A; oven: 40° C.; flow rate: 3.0 ml/min; UV detection: 210 nm.

Method 8 (LC-MS):

MS instrument type: Waters ZQ; HPLC instrument type: Waters Alliance2795; column: Phenomenex Onyx Monolithic C18, 100 mm×3 mm; mobile phaseA: 1 l of water+0.5 ml of 50% strength formic acid, mobile phase B: 1 lof acetonitrile+0.5 ml of 50% strength formic acid; gradient: 0.0 min90% A→2 min 65% A→4.5 min 5% A→6 min 5% A; flow rate: 2 ml/min; oven:40° C.; UV detection: 210 nm.

Method 9 (LC-MS):

Instrument: Waters Acquity SQD HPLC System; column: Waters Acquity HPLCHSS T3 1.8μ, 50 mm×1 mm; mobile phase A: 1 l of water+0.25 ml of 99%strength formic acid, mobile phase B: 1 l of acetonitrile+0.25 ml of 99%strength formic acid; gradient: 0.0 min 90% A→1.2 min 5% A→2.0 min 5% A;flow rate: 0.40 ml/min; oven: 50° C.; UV detection: 210-400 nm.

Method 10 (LC-MS):

Instrument: Micromass Quattro Micro MS with HPLC Agilent Series 1100;column: Thermo Hypersil GOLD 3p 20 mm×4 mm; mobile phase A: 1 l ofwater+0.5 ml of 50% strength formic acid, mobile phase B: 1 l ofacetonitrile+0.5 ml of 50% strength formic acid; gradient: 0.0 min 100%A→3.0 min 10% A→4.0 min 10% A→4.01 min 100% A (flow rate 2.5ml/min)→5.00 min 100% A; oven: 50° C.; flow rate: 2 ml/min; UVdetection: 210 nm.

Starting Materials and Intermediates Example 1A4-Methyl-3-(methylsulfanyl)benzonitrile

Method A:

The reaction was carried out under argon. 3-Fluoro-4-methylbenzonitrile(3000 mg, 22.2 mmol) and sodium methanethiolate (1572 mg, 20.2 mmol)were initially charged in DMF (30 ml), potassium carbonate (6973 mg,50.5 mmol) was added and the mixture was stirred under reflux overnight.The reaction was then concentrated, the residue was suspended inmethylene chloride/methanol (10:1) and the insoluble potassium carbonatewas filtered off. The filtrate was reconcentrated and the residue waschromatographed on silica gel (mobile phase: cyclohexane/ethyl acetate10:1). This gave 2.51 g (64% of theory) of the desired compound.

Method B:

The reaction was carried out with the aid of a washer filled with sodiumhypochlorite solution. 3-Fluoro-4-methylbenzonitrile (200 g, 1479.9mmol) was initially charged in DMF (1.5 liters) and warmed to 40° C.,and sodium methanethiolate (altogether 126.8 g, 1627.9 mmol) was added alittle at a time (about 25 g per portion). During the addition, thetemperature increased to 100° C. The reaction mixture was stirredinitially at a bath temperature of 175° C. for 1.5 h and then at roomtemperature overnight. The reaction mixture was then poured into water(7.5 liters) and extracted twice with ethyl acetate (1875 ml each). Thecombined organic phases were washed with saturated sodium chloridesolution (1875 ml) and concentrated on a rotary evaporator, and theresidue was chromatographed on silica gel (mobile phase: petroleumether/ethyl acetate 95:5, about 30 liters). Removal of the solvent on arotary evaporator and drying under high vacuum gave 172 g (71% oftheory) of the desired compound.

GC-MS (Method 1): R_(t)=5.25 min; MS (ESIpos): m/z (%)=163.0 (100) [M]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=2.30 (s, 3H), 2.54 (s, 3H), 7.38 (d, 1H),7.52 (dd, 1H), 7.58 (br. s, 1H).

Example 2A 4-Methyl-3-(methylsulfonyl)benzonitrile

Method A:

4-Methyl-3-(methylsulfanyl)benzonitrile (14 050 mg, 80.1 mmol; Example1A) was dissolved in dichloromethane (700 ml) and cooled to 0° C., and3-chloroperbenzoic acid (50 923 mg, 206.6 mmol) was added slowly. Themixture was then stirred initially at 0° C. for 40 min and then at roomtemperature overnight. The precipitated 3-chlorobenzoic acid wasfiltered off, the filtrate was washed with 1N aqueous sodium hydroxidesolution and the organic phase was dried over sodium sulfate andconcentrated. The residue was purified by silica gel chromatography(mobile phase: cyclohexane/ethyl acetate 1:1, 1:2). This gave 13.65 g(81% of theory) of the desired compound.

Method B:

3-Chloroperbenzoic acid (2501 g, 10 144.4 mmol) was dissolved in 27.2liters of dichloromethane and cooled to 10° C., and4-methyl-3-(methylsulfanyl)benzonitrile (552 g, 3381.5 mmol; Example 1A)was added a little at a time. After the addition had ended, the mixturewas stirred at RT for 5 h. The precipitated 3-chlorobenzoic acid wasfiltered off with suction and the solid was washed with dichloromethane(3 liters). The combined filtrates were stirred with 1N aqueous sodiumhydroxide solution (15 liters), the mixture was filtered and the organicphase was separated off. The latter was once more stirred with 1Naqueous sodium hydroxide solution (15 liters), separated from the sodiumhydroxide solution, dried and concentrated on a rotary evaporator. Theresidue was suspended in diethyl ether (4 liters), stirred for 10 minand then filtered. The solid was washed with a little diethyl ether anddried under high vacuum. This gave 613 g (93% of theory) of the desiredcompound.

GC-MS (Method 1): R_(t)=6.59 min; MS (ESIpos): m/z (%)=195.0 (100) [M]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=2.30 (s, 3H), 2.54 (s, 3H), 7.38 (d, 1H),7.52 (dd, 1H), 7.58 (br. s, 1H).

Example 3A 4-[2-(Dimethylamino)ethenyl]-3-(methylsulfonyl)benzonitrile

Method A:

The reaction was carried out under argon. At 140° C.,4-methyl-3-(methylsulfonyl)benzonitrile (13 000 mg, 66.6 mmol; Example2A) and 1,1-dimethoxy-N,N-dimethylmethanamine (10 315 mg, 86.6 mmol)were stirred in DMF (200 ml) for 14 h. To bring the reaction tocompletion, more 1,1-dimethoxy-N,N-dimethylmethanamine (3967 mg, 33.3mmol) was then added, and the mixture was stirred at 140° C. for afurther 24 h. The DMF was then removed on a rotary evaporator, and theresidue was reacted without further purification in the next step.

Method B:

The reaction was carried out under argon.4-Methyl-3-(methylsulfonyl)benzonitrile (612 g, 3134.6 mmol; Example 2A)was initially charged in DMF (6.12 liters),1,1-dimethoxy-N,N-dimethylmethanamine (859 g, 7209.5 mmol) was added andthe mixture was stirred at 140° C. for 7 h. The reaction mixture wasthen poured into 35 liters of 10% strength sodium chloride solution andextracted twice with in each case 10 liters of ethyl acetate. Thecombined organic phases were washed with saturated sodium chloridesolution (5 liters), dried and concentrated on a rotary evaporator, andthe residue was dried under high vacuum overnight. This gave 1098 g (98%of theory) of the desired compound.

GC-MS (Method 1): R_(t)=8.95 min; MS (ESIpos): m/z (%)=250.0 (10) [M]⁺.

Example 4A 4-Formyl-3-(methylsulfonyl)benzonitrile

Method A:

4-[2-(Dimethylamino)ethenyl]-3-(methylsulfonyl)benzonitrile (16 666 mg,66.6 mmol; Example 3A) was initially charged in water/THF (1:1, 500 ml),sodium periodate (42 722 mg, 199.7 mmol) was added and the mixture wasstirred at room temperature overnight. The precipitated solid wasfiltered off and washed with ethyl acetate. The combined organic phaseswere washed with saturated sodium bicarbonate solution and saturatedsodium chloride solution, dried over sodium sulfate, filtered andconcentrated. The residue was purified by silica gel chromatography(mobile phase: cyclohexane/ethyl acetate 1:1). This gave 4.6 g (33% oftheory) of the desired compound.

Method B:

4-[2-(Dimethylamino)ethenyl]-3-(methylsulfonyl)benzonitrile (1098 g,3070.5 mmol; Example 3A) was initially charged in THF/water (1:1, 13.8liters), sodium periodate (1970 g, 9211.4 mmol) was added and themixture was stirred at room temperature for 1 h. The precipitated solidwas filtered off with suction and washed with ethyl acetate (17 liters).Water (17 liters) was added to the combined filtrates, and after theextraction the aqueous phase was removed. The organic phase was washedwith saturated sodium bicarbonate solution (8.5 liters) and saturatedsodium chloride solution (8.5 liters), and then dried and concentratedon a rotary evaporator. The residue was purified by silica gelchromatography (mobile phase: dichloromethane/ethyl acetate 9:1, 60liters). The product fractions were concentrated, the residue wassuspended in petroleum ether and then filtered off with suction and thesolid was dried under high vacuum overnight. This gave 436 g (65% oftheory) of the desired compound.

GC-MS (Method 1): R_(t)=6.89 min; MS (ESIpos): m/z (%)=191.1 (15)[M-18]⁺, 161.0 (100).

¹H-NMR (400 MHz, DMSO-d₆): δ=3.57 (s, 3H), 8.10 (d, 1H), 8.39 (dd, 1H),8.45 (d, 1H), 10.63 (s, 1H).

Example 5A(4S)-4-[4-Cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The reaction was carried out under argon. Allyl(4S)-4-[4-cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate(800 mg, 1.54 mmol; Example 4) and morpholine (1.5 eq., 201 mg, 2.31mmol) were initially charged in dry THF (25 ml) at RT. The reactionmixture was degassed repeatedly (evacuation followed by venting withargon). Under protective gas, tetrakis(triphenylphosphine)palladium(0)(0.05 eq., 89 mg, 0.077 mmol) was added, and the reaction mixture wasstirred at RT for 90 min (HPLC control). The reaction mixture was thenconcentrated and the residue was taken up in ethyl acetate (500 ml). Theorganic phase was washed with saturated ammonium chloride solution (50ml), with water (50 ml) and with conc. sodium chloride solution (50 ml),dried over sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by preparative HPLC (column: GromsilC-18 10 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). Thisgave a colorless amorphous solid (696 mg, purity 86%, 81% of theory).

LC-MS (Method 6): R_(t)=2.15 min; MS (ESIpos): m/z (%)=480.1 (100)[M+H]⁺; MS (ESIneg): m/z (%)=478.1 (100) [M−H]⁻

¹H-NMR (400 MHz, DMSO-d₆): δ=2.14 (s, 3H), 3.45 (s, 3H), 6.35 (d, 1H),7.14 (d, 1H), 7.72 (m, 2H), 7.80 (m, 1H), 7.86 (s, 1H), 8.11 (d, 1H),8.27 (d, 1H), 8.36 (s, 1H), 12.64 (br. s, 1H).

Example 6A 4-Nitrophenyl(6S)-5-cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidine-1(2H)-carboxylate

(4S)-4-[4-Cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile(1.00 g, 2.17 mmol; Example 6) and triethylamine (659 mg, 6.52 mmol)were, together with a spatula tip of 4-N,N-dimethylaminopyridine,suspended in dichloromethane (8.3 ml). 4-Nitrophenyl chloroformate (875mg, 4.34 mmol) was then added. The resulting solution was stirred atroom temperature for 5 min, and water (1 ml) was then added.Furthermore, toluene (7 ml) was added to the contents of the flask, andthe mixture was concentrated under reduced pressure. The residue wassubjected to flash chromatography on silica gel (mobile phase:dichloromethane). The concentrated product fractions were trituratedwith ethanol (20 ml), and the resulting solid was filtered off withsuction. This gave the target compound (559 mg, 39% of theory).

HPLC (Method 3): R_(t)=4.92 min (94%); MS (ESIpos): m/z (%)=626.3 (18)[M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=1.88 (s, 3H), 3.39 (s, 3H), 7.31 (s, 1H),7.37 (d, 2H), 7.78-8.22 (m, 5H), 8.24 (d, 2H), 8.41 (d, 1H), 8.51 (s,1H).

Example 7A (rac)-2,3-Dibromopropyl6-(bromomethyl)-4-[4-cyano-2-(methylsulfonyl)phenyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate

At 0° C., a solution of bromine (335.6 mg, 2.1 mmol, 2.1 eq.) inchloroform (2 ml) was added dropwise to a solution of allyl(rac)-4-[4-cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate(Example 3; 519 mg, 1.0 mmol) in chloroform (10 ml). The reactionmixture was stirred at RT overnight. HPLC control then showed completeconversion. The mixture was diluted with dichloromethane (50 ml) andthen washed with 10% strength aqueous sodium sulfite solution (2×50 ml)and saturated aqueous sodium chloride solution (30 ml). The organicphase was dried over sodium sulfate, filtered and concentrated underreduced pressure, and the residue was dried under high vacuum. This gavea solid as crude product (880 mg, quant., purity according to LC-MSabout 94%) which was reacted further without further purification.

LC-MS (Method 6): R_(t)=2.79 min; MS (ESIpos): m/z (%)=759.8 (100)[M+H]⁺; MS (ESIneg): m/z (%)=714.9 (90), 758.0 (100) [M−H]⁻.

Example 8A 3-Fluoro-4-formylbenzonitrile

The reaction was carried out under argon. 3-Fluoro-4-methylbenzonitrile(121 g, 895 mmol) and N,N-dimethylformamide dimethyl acetal (245 g, 2.06mol) were dissolved in DMF (1.8 liters) and stirred under refluxovernight. The contents of the flask was then poured into water (2liters), the mixture was extracted twice with ethyl acetate and thecombined organic phases were washed with saturated sodium chloridesolution. The organic phase was concentrated, and the residue wasdissolved again in THF/water (1:1, 2.7 liters). Sodium periodate (503 g,2.35 mol) was added, and the mixture was stirred at room temperature forone hour. The precipitate was then separated off, and the filtrate wasrecovered and extracted repeatedly with ethyl acetate. The combinedorganic phases were washed once with saturated sodium bicarbonatesolution and once with saturated sodium chloride solution, dried andconcentrated to give an oil. This was purified by column chromatographyon silica gel (mobile phase: petroleum ether/dichloromethane 6:4, then4:6, finally pure dichloromethane). The product fractions wereconcentrated. This gave 28.0 g (20% of theory) of the target compound asa white crystalline solid.

GC-MS (Method 1): R_(t)=3.63 min; MS (ESIpos): m/z (%)=149.0 (48) [M]⁺,150.0 (5) [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=7.89 (d, 1H), 8.00 (t, 1H), 8.11 (d, 1H),10.24 (s, 1H).

Example 9A 4-Formyl-3-(methylsulfanyl)benzonitrile

3-Fluoro-4-formylbenzonitrile (2.00 g, 13.4 mmol; Example 8A) wasdissolved in DMSO (27 ml), and sodium methanethiolate (1.50 g, 21.5mmol) was added with ice-bath cooling. The mixture was stirred for 45min and then diluted with water (100 ml). The resulting precipitatedproduct was filtered off with suction, washed with water and dried underreduced pressure. This gave 1.36 g (51% of theory) of the targetcompound as a yellow crystalline solid.

GC-MS (Method 1): R_(t)=5.90 min; MS (ESIpos): m/z (%)=177.0 (100) [M]⁺,178.0 (11) [M+H]⁺.

Example 10A(rac)-4-[4-Cyano-2-(methylsulfanyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

Allyl(rac)-4-[4-cyano-2-(methylsulfanyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate(750 mg, 1.54 mmol; Example 39) was dissolved in THF (10 ml), andmorpholine (201 mg, 2.308 mmol) was added. The reaction solution wassaturated with argon (argon was bubbled through the solution for 30min). Tetrakis(triphenylphosphine)palladium(0) (7.47 mg, 0.006 mmol) wasthen added, and the mixture was stirred at RT overnight. Since, by HPLCcontrol, only little conversion could be observed, moretetrakis(triphenylphosphine)palladium(0) (7.47 mg, 0.006 mmol) wasadded, and the mixture was stirred at RT for a further 3 h. The contentsof the flask was then filtered through kieselguhr, and the residue waswashed with THF. The filtrate was concentrated under reduced pressureand the residue was recrystallized from diethyl ether (15 ml). Thecrystals were filtered off with suction and dried under high vacuum.This gave 663 mg (96% of theory) of the target compound.

LC-MS (Method 4): R_(t)=1.10 min; MS (ESIpos): m/z (%)=448.0 (100)[M+H]⁺; MS (ESIneg): m/z (%)=446.3 (100) [M−H]⁻.

Example 11A(4S)-4-[4-Cyano-2-(methylsulfanyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

(rac)-4-[4-Cyano-2-(methylsulfanyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (663 mg, 1.48 mmol; Example 10A) was separated into the enantiomersby preparative HPLC chromatography on a chiral phase [column: chiralsilica gel phase based on the selectorpoly(N-methacryloyl-D-leucine-dicyclopropylmethylamide); columndimensions: 670 mm×40 mm; sample preparation: the sample was dissolvedin 20 ml of methanol/ethyl acetate 1:3; injection volume: 15 ml;gradient elution: ethyl acetate (100%)→methanol (100%); flow rate: 80ml/min; temperature: 25° C.; detection: 260 nm]. This gave 279 mg (84%of theory, 96% ee) of the 4S-enantiomer as a colorless amorphous solid.

HPLC (Method 2): R_(t)=4.15 min.

MS (DCI/NH₃): m/z=448.1 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=2.07 (s, 3H), 2.57 (s, 3H), 5.80 (d, 1H),7.62-7.83 (m, 7H), 8.02 (d, 1H).

Optical rotation: [α]²⁰ _(Na)=+14.0° (c=0.210 in DMF).

Example 12A tert-Butyl[(3R)-1-{[(6S)-5-cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl}-3,6-dihydropyrimidin-1(2H)-yl]carbonyl]piperidin-3-yl]carbamate

4-Nitrophenyl(6S)-5-cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidine-1(2H)-carboxylate(Example 6A; 100 mg, 0.16 mmol) was dissolved in acetonitrile (1.25 ml),and tert-butyl (3R)-piperidin-3-ylcarbamate (96.1 mg, 0.48 mmol) wasadded with stirring. The mixture was stirred at RT overnight. Thereaction mixture was then purified directly by preparative HPLC (column:Kromasil C18, 125 mm×20 mm, 5 μm; mobile phase A: water with 0.01%formic acid, mobile phase B: acetonitrile; gradient: 0 min 10% B→2 min10% B→9 min 90% B→12 min 90% B→12.1 min 10% B→15 min 10% B; flow rate:0.35 ml/min; UV detection: 254 nm). The product fractions were combinedand concentrated under reduced pressure. This gave 81 mg (74% of theory)of the target compound.

HPLC (Method 2): R_(t)=4.90 min.

MS (ESIpos): m/z (%)=709.1 (35) [M+Na]⁺.

Example 13A

(rac)-Ethyl6-(bromomethyl)-4-[4-cyano-2-(methylsulfonyl)phenyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate

(rac)-Ethyl4-[4-cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate(Example 115; 3.00 g, 5.62 mmol) was dissolved in chloroform (49.9 ml),and the solution was cooled to 0° C. on an ice bath. Bromine (987 mg,6.18 mmol) was then added dropwise. Subsequently, the ice bath wasremoved and the reaction mixture was stirred at RT for 1 h. Sodiumthiosulfate solution (50 ml) was then added, and the organic phase wasseparated off, dried over sodium sulfate and concentrated under reducedpressure. The residue was triturated with diethyl ether, and the solidwas filtered off with suction and washed with diethyl ether. This gave2.96 g (90% of theory) of the target compound as a yellow crystallinesolid.

HPLC (Method 2): R=4.73 min.

MS (ESIpos): m/z (%)=586 (57), 588 (62) [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=0.97 (t, 3H), 3.50 (s, 3H), 3.94-4.09 (q,2H), 4.18 (d, 1H), 4.70 (d, 1H), 6.48 (s, 1H), 7.47 (s, 1H), 7.70-7.95(m, 4H), 8.07 (br. s, 1H), 8.31 (d, 1H), 8.42 (s, 1H).

Example 14A 2,3-Dibromopropyl(4S)-6-(bromomethyl)-4-[4-cyano-2-(methylsulfonyl)phenyl]-3-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate

At 0° C., a solution of bromine (320.8 mg, 2.0 mmol, 2.1 eq.) inchloroform (5 ml) was added dropwise to a solution of allyl(4S)-4-[4-cyano-2-(methylsulfonyl)phenyl]-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate(510 mg, 0.96 mmol) in chloroform (15 ml). The reaction mixture wasstirred at RT for 2 h. HPLC control then showed complete conversion. Themixture was diluted with dichloromethane (100 ml) and subsequentlywashed with 10% strength aqueous sodium sulfite solution (2×50 ml) andsaturated aqueous sodium chloride solution (30 ml). The organic phasewas dried over sodium sulfate, filtered and concentrated under reducedpressure, and the residue was dried under high vacuum. This gave a solidas a crude product (803 mg, quant.) which was reacted further withoutfurther purification.

LC-MS (Method 4): R_(t)=1.50 min; MS (ESIpos): m/z (%)=773.7 (100)[M+H]⁺.

Example 15A 4-(1,3-Dioxan-2-yl)-3-fluorobenzonitrile

4-Cyano-2-fluorobenzaldehyde (65 g, 436 mmol) and 1,3-propanediol (36.5g, 479 mmol; 1.1 eq.) were, together with 4-toluenesulfonic acidmonohydrate (1.66 g, 8.72 mmol; 0.02 eq.), initially charged in toluene(1000 ml) and stirred at boiling point on a water separator for 6 h. Thereaction mixture was then washed with saturated sodium bicarbonatesolution (3×300 ml) and saturated sodium chloride solution (3×300 ml).The organic phase was dried over sodium sulfate and concentrated. Thetitle compound was obtained as a solid (92 g, quant.).

GC-MS (Method 1): R_(t)=5.49 min; MS (ESIpos): m/z (%)=206.1 (100)[M−H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=1.46 (d, 1H), 2.00 (m, 1H), 4.00 (t, 2H),4.15 (dd, 2H), 5.80 (s, 1H), 7.70 (m, 2H), 7.90 (m, 1H).

Example 16A 4-(1,3-Dioxan-2-yl)-3-(ethylsulfanyl)benzonitrile

The reaction was carried out under argon.4-(1,3-Dioxan-2-yl)-3-fluorobenzonitrile (4.14 g, 20 mmol) and sodiumethanethiolate (1.68 g, 20 mmol; 1 eq.) were initially charged in DMF(100 ml). Potassium carbonate (6.91 g, 50 mmol; 2.5 eq.) was added atRT, and the mixture was stirred at 100° C. for 5 h. TLC control thenshowed complete conversion. The mixture was concentrated and the residuewas subjected to flash chromatography on silica gel (mobile phase:cyclohexane→cyclohexane/ethyl acetate 4:1). The title compound wasobtained as a solid (4.8 g, 97% of theory).

MS (DCI/NH₃): m/z=266.1 [M+NH₃]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=1.25 (t, 3H), 1.45 (d, 1H), 2.00 (m, 1H),3.10 (q, 2H), 4.00 (m, 2H), 4.15 (m, 2H), 5.70 (s, 1H), 7.65 (m, 2H),7.85 (m, 1H).

Example 17A 4-(1,3-Dioxan-2-yl)-3-(ethylsulfonyl)benzonitrile

4-(1,3-Dioxan-2-yl)-3-(ethylsulfanyl)benzonitrile (1060 mg, 4.25 mmol)was initially charged in dichloromethane (45 ml). At 0° C., MCPBA (2641mg, 15.3 mmol; 3.6 eq.) was added a little at a time. The mixture wasslowly warmed to RT and then stirred for 16 h. The reaction mixture wasthen diluted with dichloromethane (200 ml), subsequently washed with 5%strength aqueous sodium carbonate solution (6×50 ml) and saturatedsodium chloride solution (50 ml), dried over solid sodium sulfate,filtered and concentrated. The resulting product (1230 mg, quant.,purity according to LC-MS 100%) was reacted further as such.

LC-MS (Method 4): R_(t)=0.97 min; MS (ESIpos): m/z (%)=208.0 (100),282.1 (20) [M+H]⁺

MS (DCI/NH₃): m/z (%)=282.0 (15) [M+H]⁺, 299.1 (100) [M+NH₄]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=1.13 (t, 3H), 1.50 (d, 1H), 2.05 (m, 1H),3.40 (q, 2H), 4.00 (m, 2H), 4.20 (m, 2H), 6.30 (s, 1H), 8.00 (m, 2H),8.25 (m, 1H).

Example 18A 3-(Ethylsulfonyl)-4-formylbenzonitrile

In an Emrys microwave, 4-(1,3-dioxan-2-yl)-3-(ethylsulfonyl)benzonitrile(1230 mg, 4.4 mmol) and pyridinium 4-toluenesulfonate (814 mg, 3.3 mmol;0.75 eq.) in acetone/water (1:1, 20 ml) were heated with stirring at165° C. for 7 min. The reaction mixture was then added to water (150 ml)and extracted with ethyl acetate (6×50 ml). The combined organic phaseswere then washed with saturated sodium chloride solution (30 ml), driedover sodium sulfate, filtered and concentrated under reduced pressure.The crude product was subjected to flash chromatography on silica gel(mobile phase: cyclohexane→cyclohexane/ethyl acetate 3:2). The titlecompound was isolated as a solid (0.89 g, 90% of theory).

¹H-NMR (400 MHz, DMSO-d₆): δ=1.22 (t, 3H), 3.65 (q, 2H), 8.10 (m, 2H),8.40 (m, 1H), 10.60 (s, 1H).

Example 19A(rac)-4-[4-Cyano-2-(ethylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The reaction was carried out under argon. Allyl(rac)-4-[4-cyano-2-(ethylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate(1300 mg, 2.44 mmol) and morpholine (1.5 eq., 318 mg, 3.66 mmol) wereinitially charged in dry THF (65 ml) at RT. The reaction mixture wasdegassed repeatedly (evacuation followed by venting with argon). Underprotective gas, tetrakis(triphenylphosphine)palladium(0) (0.05 eq., 141mg, 0.122 mmol) was added, and the reaction mixture was stirred at RTfor 16 h (HPLC control). The mixture was then concentrated, and theresidue was taken up in ethyl acetate (100 ml). The organic phase waswashed with 0.1 N hydrochloric acid (2×40 ml) and with saturated sodiumchloride solution (3×30 ml), dried over sodium sulfate, filtered andconcentrated under reduced pressure. Methanol (10 ml) was added to theresidue. The precipitated product was filtered off with suction andwashed with methanol (2×5 ml). The title compound was isolated as asolid (1120 mg, 93% of theory).

LC-MS (Method 5): R_(t)=1.76 min; MS (ESIpos): m/z (%)=494.1 (100)[M+H]⁺; MS (ESIneg): m/z (%)=492.1 (100) [M−H]⁻

¹H-NMR (400 MHz, DMSO-d₆): δ=1.70 (t, 3H), 2.13 (s, 3H), 3.60 (m, 2H),6.21 (br. d, 1H), 7.00 (d, 1H), 7.70-7.85 (m, 4H), 8.10 (br. d, 1H),8.30-8.35 (m, 2H), 12.65 (br. s, 1H).

Example 20A 4-(1,3-Dioxan-2-yl)-3-[(2-hydroxyethyl)sulfanyl]benzonitrile

The reaction was carried out under argon.4-(1,3-Dioxan-2-yl)-3-fluorobenzonitrile (2.07 g, 10 mmol; 1.1 eq.) and2-mercaptoethanol (0.71 g, 9.1 mmol; 1 eq.) were initially charged inDMF (50 ml). Potassium carbonate (3.14 g, 22.7 mmol; 2.5 eq.) was addedat RT, and the mixture was stirred at boiling point for 1 h. TLC controlthen showed complete conversion. The mixture was concentrated and theresidue was subjected to flash chromatography on silica gel (mobilephase: cyclohexane→cyclohexane/ethyl acetate 1:2). The title compoundwas obtained as a solid (2.33 g, 88% of theory).

¹H-NMR (400 MHz, DMSO-d₆): δ=1.45 (d, 1H), 2.00 (m, 1H), 3.14 (t, 2H),3.55 (q, 2H), 4.00 (m, 2H), 4.15 (m, 2H), 5.00 (t, 1H), 5.70 (s, 1H),7.65 (m, 2H), 7.90 (m, 1H).

Example 21A 4-(1,3-Dioxan-2-yl)-3-[(2-hydroxyethyl)sulfonyl]benzonitrile

4-(1,3-Dioxan-2-yl)-3-[(2-hydroxyethyl)sulfanyl]benzonitrile (2000 mg,7.55 mmol) was initially charged in dichloromethane (60 ml). At 0° C.,MCPBA (4460 mg, 18.1 mmol; 2.4 eq.) was added a little at a time. Thereaction mixture was slowly warmed to RT and then stirred for 16 h. Thereaction mixture was then diluted with dichloromethane (100 ml),subsequently washed with 5% strength aqueous sodium bicarbonate solution(4×50 ml) and saturated sodium chloride solution (50 ml), dried oversolid sodium sulfate, filtered and concentrated. The product obtained(2.25 g, quant., purity according to LC-MS 100%) was reacted further assuch.

LC-MS (Method 5): R_(t)=1.17 min; MS (ESIpos): m/z=298 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=1.50 (d, 1H), 2.05 (m, 1H), 3.60 (t, 2H),3.70 (q, 2H), 4.00 (m, 2H), 4.20 (m, 2H), 4.90 (t, 1H), 6.30 (s, 1H),8.00 (d, 1H), 8.25 (dd, 1H), 8.30 (d, 1H).

Example 22A 3-[(2-Hydroxyethyl)sulfonyl]-4-formylbenzonitrile

In an Emrys microwave,4-(1,3-dioxan-2-yl)-3-[(2-hydroxyethyl)sulfonyl]benzonitrile (1970 mg,6.6 mmol) and pyridinium 4-toluenesulfonate (1249 mg, 4.97 mmol; 0.75eq.) in acetone/water (1:1, 30 ml) were heated with stirring at 160° C.for 5 min. The reaction mixture was then added to water (200 ml) andextracted with ethyl acetate (8×50 ml). The combined organic phases werethen washed with saturated sodium chloride solution (2×50 ml), driedover sodium sulfate, filtered and concentrated under reduced pressure.To increase the yield, the sodium chloride wash solution was reextractedwith ethyl acetate. The title compound was obtained as a solid (1.57 g,99% of theory).

MS (DCI/NH₃): m/z=257.1 [M+NH₄]⁺.

Example 23A(rac)-4-[4-Cyano-2-((2-hydroxyethyl)sulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The reaction was carried out under argon. Allyl(rac)-4-[4-cyano-2-((2-hydroxyethyl)sulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate(150 mg, 0.273 mmol) and morpholine (1.5 eq., 35.6 mg, 0.409 mmol) wereinitially charged in dry THF (4 ml) at RT. The reaction mixture wasdegassed repeatedly (evacuation followed by venting with argon). Underprotective gas, tetrakis(triphenylphosphine)palladium(0) (0.05 eq., 15.8mg, 0.014 mmol) was added, and the reaction mixture was stirred at RTfor 1 h (HPLC control). The mixture was then concentrated, and theresidue was taken up in ethyl acetate (60 ml). The organic phase waswashed repeatedly with saturated ammonium chloride solution (3×20 ml),water (20 ml) and saturated sodium chloride solution (20 ml), dried oversodium sulfate, filtered and concentrated under reduced pressure. Thecrude product was purified by preparative HPLC (column: Gromsil C-18;mobile phase: acetonitrile/water+0.1% TFA 10:90→80:20). The titlecompound was obtained as a solid (60 mg, 43% of theory).

LC-MS (Method 6): R_(t)=2.04 min; MS (ESIpos): m/z (%)=510.1 (100)[M+H]⁺; MS (ESIneg): m/z (%)=508.1 (100) [M−H]⁻.

Example 24A(rac)-4-{2-[(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)sulfonyl]-4-cyanophenyl}-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide

The reaction was carried out under argon.(rac)-4-[4-Cyano-2-((2-hydroxyethylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide(600 mg, 1.18 mmol) was initially charged in DMF (40 ml). At 0° C.,imidazole (803 mg, 11.8 mmol; 10 eq.) was added, followed bytert-butyl(dimethyl)silyl chloride (1245 mg, 8.26 mmol; 7 eq.). Themixture was slowly warmed to RT and subsequently stirred for 16 h. Thereaction mixture was then concentrated under high vacuum, the residuewas taken up in ethyl acetate (200 ml) and the organic phase was washedwith ammonium chloride solution (3×50 ml) and saturated sodium chloridesolution (50 ml). The organic phase was then dried over sodium sulfate,filtered and concentrated. This gave a solid as crude product (740 mg,quant.), which was reacted without further purification.

LC-MS (Method 6): R_(t)=2.69 min; MS (ESIpos): m/z (%)=623.2 (100)[M+H]⁺.

Example 25A(rac)-4-{2-[(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)sulfonyl]-4-cyanophenyl}-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile

The reaction was carried out under argon.(rac)-4-{2-[(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)sulfonyl]-4-cyanophenyl}-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide(740 mg, 1.18 mmol) was initially charged in dry THF (30 ml),methoxy-carbonylsulfamoyltriethylammonium hydroxide (Burgess reagent;1.699 g, 7.13 mmol; 6 eq.) was added and the mixture was stirred at RT.After 75 min, HPLC control showed complete conversion. The reactionmixture was then taken up in ethyl acetate (150 ml). The organic phasewas washed with saturated sodium chloride solution (3×50 ml), dried oversolid sodium sulfate, filtered and concentrated. The residue wassubjected to flash chromatography on silica gel (mobile phase:cyclohexane/ethyl acetate 1:1). The title compound was obtained as acolorless solid (550 mg, 77% of theory).

LC-MS (Method 6): R_(t)=2.96 min; MS (ESIpos): m/z (%)=605.2 (100)[M+H]⁺; MS (ESIneg): m/z (%)=560.2 (100), 603.3 (50) [M−H]⁻.

Example 26A 4-(1,3-Dioxan-2-yl)-3-(propan-2-ylsulfanyl)benzonitrile

The reaction was carried out under argon.4-(1,3-Dioxan-2-yl)-3-fluorobenzonitrile (5.51 g, 27 mmol) and sodium2-propanethiolate (2.90 g, 26.6 mmol, purity 90%; 1 eq.) were initiallycharged in DMF (125 ml). Potassium carbonate (9.19 g, 66.5 mmol; 2.5eq.) was added at RT, and the mixture was stirred at 100° C. for 4 h.TLC control then showed complete conversion. The reaction mixture wasconcentrated and the residue was subjected to flash chromatography onsilica gel (mobile phase: cyclohexane→cyclohexane/ethyl acetate 4:1).The title compound was isolated as a solid (6.72 g, 96% of theory).

¹H-NMR (400 MHz, DMSO-d₆): δ=1.25 (d, 6H), 1.45 (d, 1H), 2.00 (m, 1H),3.70 (m, 1H), 4.00 (m, 2H), 4.15 (m, 2H), 5.75 (s, 1H), 7.70 (m, 2H),7.95 (m, 1H).

Example 27A 4-(1,3-Dioxan-2-yl)-3-(propan-2-ylsulfonyl)benzonitrile

4-(1,3-Dioxan-2-yl)-3-(propan-2-ylsulfanyl)benzonitrile (1090 mg, 4.14mmol) was initially charged in dichloromethane (40 ml). At 0° C., MCPBA(2449 mg, 9.9 mmol; 2.4 eq.) was added a little at a time. The mixturewas slowly warmed to RT and then stirred for 16 h. The reaction mixturewas then diluted with dichloromethane, subsequently washed withsaturated sodium bicarbonate solution (50 ml), 5% strength aqueoussodium carbonate solution (5×50 ml) and saturated sodium chloridesolution (50 ml), dried over solid sodium sulfate, filtered andconcentrated. The product obtained in this manner (1.17 g, 96%, purityaccording to LC-MS 89%) was reacted without further purification.

LC-MS (Method 5): R_(t)=1.63 min; MS (ESIpos): m/z (%)=240.3 (100),296.3 (40) [M+H]⁺

MS (DCI/NH₃): m/z (%)=296.1 (25) [M+H]⁺, 313.1 (100) [M+NH₄]⁺.

Example 28A 4-Formyl-3-[(1-methylethyl)sulfonyl]benzonitrile

In an Emrys microwave,4-(1,3-dioxan-2-yl)-3-(propan-2-ylsulfonyl)benzonitrile (1090 mg, 3.7mmol) and pyridinium 4-toluenesulfonate (696 mg, 2.8 mmol; 0.75 eq.) inacetone/water (1:1, 15 ml) were heated with stirring at 165° C. for 7min. The reaction mixture was then added to water (150 ml) and extractedwith dichloromethane (9×30 ml). The combined organic phases weresubsequently washed with saturated sodium chloride solution (30 ml),dried over sodium sulfate, filtered and concentrated under reducedpressure. The crude product was subjected to flash chromatography onsilica gel (mobile phase: cyclohexane→cyclohexane/ethyl acetate 3:2).The title compound was isolated as a solid (0.764 g, 87% of theory).

¹H-NMR (400 MHz, DMSO-d₆): δ=1.25 (d, 6H), 3.80 (m, 1H), 8.10 (m, 1H),8.40 (m, 2H), 10.60 (s, 1H).

Example 29A(rac)-4-{4-Cyano-2-[(1-methylethyl)sulfonyl]phenyl}-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The reaction was carried out under argon. Allyl4-{4-cyano-2-[(1-methylethyl)sulfonyl]phenyl}-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate(1200 mg, 2.19 mmol) and morpholine (1.5 eq., 286 mg, 3.30 mmol) wereinitially charged in dry THF (60 ml) at RT. The reaction mixture wasdegassed repeatedly (evacuation followed by venting with argon). Underprotective gas, tetrakis(triphenylphosphine)palladium(0) (0.05 eq., 127mg, 0.110 mmol) was added, and the reaction mixture was stirred at RTfor 0.5 h (HPLC control). The mixture was then concentrated, and theresidue was taken up in ethyl acetate (100 ml). The organic phase waswashed with 0.1 N hydrochloric acid (40 ml) and with saturated sodiumchloride solution (3×30 ml), dried over sodium sulfate, filtered andconcentrated under reduced pressure. Methanol (10 ml) was added to theresidue. The precipitated product was filtered off with suction andwashed with a little methanol (2×5 ml). The title compound was isolatedas a solid (1060 mg, 95% of theory).

LC-MS (Method 5): R_(t)=1.81 min; MS (ESIpos): m/z (%)=508.1 (100)[M+H]⁺; MS (ESIneg): m/z (%)=506.1 (100) [M−H]⁻.

Example 30A 4-(1,3-Dioxan-2-yl)-3-(phenylsulfanyl)benzonitrile

The reaction was carried out under argon.4-(1,3-Dioxan-2-yl)-3-fluorobenzonitrile (207 mg, 1 mmol) and thiophenol(100 mg, 0.9 mmol; 1.1 eq.) were initially charged in DMF (3 ml).Potassium carbonate (314 mg, 2.27 mmol; 2.5 eq.) was added at RT, andthe mixture was stirred at 100° C. for 4 h. LC/MS control then showedcomplete conversion. The reaction mixture was purified directly bypreparative HPLC (column: Gromsil C-18; mobile phase:acetonitrile/water+0.1% TFA 10:90→90:10). The title compound wasobtained as a solid (238 mg, 80% of theory).

¹H-NMR (400 MHz, DMSO-d₆): δ=1.45 (d, 1H), 2.00 (m, 1H), 4.00 (m, 2H),4.15 (dd, 2H), 5.85 (s, 1H), 7.35 (s, 1H), 7.45 (m, 5H), 7.75 (m, 2H).

Example 31A 4-(1,3-Dioxan-2-yl)-3-(phenylsulfonyl)benzonitrile

4-(1,3-Dioxan-2-yl)-3-(phenylsulfanyl)benzonitrile (230 mg, 0.773 mmol)was initially charged in dichloromethane (7 ml). At 0° C., MCPBA (458mg, 1.85 mmol, content 70%; 2.4 eq.) was added a little at a time. Themixture was slowly warmed to RT and initially stirred for 3 h and thenallowed to stand at 5° C. for a further 12 h. Water (0.5 ml) was thenadded, and the reaction mixture was concentrated under reduced pressure.The crude product was purified by preparative HPLC (column: GromsilC-18; mobile phase: acetonitrile/water+0.1% TFA 10:90→75:25). The titlecompound was obtained as a solid (260 mg, quant.).

LC-MS (Method 5): R_(t)=1.84 min; MS (ESIpos): m/z (%)=330.2 (90)[M+H]⁺.

Example 32A 4-Formyl-3-(phenylsulfonyl)benzonitrile

In an Emrys microwave,4-(1,3-dioxan-2-yl)-3-(phenylsulfonyl)benzonitrile (260 mg, 0.789 mmol)and pyridinium 4-toluenesulfonate (149 mg, 0.592 mmol; 0.75 eq.) inacetone/water (1:1, 3 ml) were heated with stirring at 160° C. for 6min. The reaction mixture was then added to water (50 ml) and extractedwith ethyl acetate (8×20 ml). The combined organic phases weresubsequently washed with saturated sodium chlroide solution (2×30 ml),dried over sodium sulfate, filtered and concentrated under reducedpressure. The title compound was obtained as a solid (0.21 g, quant.).

LC-MS (Method 6): R_(t)=2.11 min; MS (ESIpos): m/z (%)=272.2 (100)[M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=7.70 (m, 2H), 7.80 (m, 1H), 8.00 (d, 1H),8.15 (m, 2H), 8.35 (dd, 1H), 8.70 (d, 1H), 10.65 (s, 1H).

Example 33A(rac)-4-{4-Cyano-2-[phenylsulfonyl]phenyl}-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The reaction was carried out under argon. Allyl4-[4-cyano-2-(phenylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate(220 mg, 0.378 mmol) and morpholine (1.5 eq., 43 mg, 0.567 mmol) wereinitially charged in dry THF (6 ml) at RT. The reaction mixture wasdegassed repeatedly (evacuation followed by venting with argon). Underprotective gas, tetrakis(triphenylphosphine)palladium(0) (0.05 eq., 22mg, 0.019 mmol) was added, and the reaction mixture was stirred at RTfor 16 h (HPLC control). The mixture was then concentrated, and theresidue was taken up in ethyl acetate (100 ml). The organic phase waswashed successively with 0.1 N hydrochloric acid (6 ml), saturatedammonium chloride solution (3×50 ml), water (30 ml) and saturated sodiumchloride solution (30 ml), dried over sodium sulfate, filtered andconcentrated under reduced pressure. The crude product was purified bypreparative HPLC (column: Gromsil C-18; mobile phase:acetonitrile/water+0.1% TFA 10:90→80:20). The target product wasobtained as a solid (104 mg, 51% of theory).

LC-MS (Method 6): R_(t)=2.35 min; MS (ESIpos): m/z (%)=542.1 (100)[M+H]⁺; MS (ESIneg): m/z (%)=540.2 (80) [M−H]⁻.

Example 34A(4S)-4-[4-Cyano-2-(methylsulfonyl)phenyl]-6-methyl-3-(methylsulfonyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The reaction was carried out under argon. Allyl(4S)-4-[4-cyano-2-(methylsulfonyl)phenyl]-6-methyl-3-(methylsulfonyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate(288 mg, 0.482 mmol) and morpholine (1.5 eq., 63 mg, 0.723 mmol) wereinitially charged in dry THF (5 ml) at RT. The reaction mixture wasdegassed repeatedly (evacuation followed by venting with argon). Underprotective gas, tetrakis(triphenylphosphine)palladium(0) (0.05 eq., 28mg, 0.024 mmol) was added, and the reaction mixture was stirred at RTfor 1.5 h (HPLC control). The mixture was then concentrated underreduced pressure, and the residue was purified by preparative HPLC(column: Gromsil C-18; mobile phase: acetonitrile/water+0.1% TFA10:90→75:25). This gave the title compound as a solid (187 mg, 70% oftheory).

LC-MS (Method 5): R_(t)=1.81 min; MS (ESIpos): m/z (%)=540.1 (100),558.1 (40) [M+H]⁺; MS (ESIneg): m/z (%)=556.2 (10) [M−H]⁻.

Example 35A(4S)-4-[4-Cyano-2-(methylsulfonyl)phenyl]-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The reaction was carried out under argon. Allyl(4S)-4-[4-cyano-2-(methylsulfonyl)phenyl]-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate(157 mg, 0.294 mmol) and morpholine (1.5 eq., 38 mg, 0.441 mmol) wereinitially charged in dry THF (5 ml) at RT. The reaction mixture wasdegassed repeatedly (evacuation followed by venting with argon). Underprotective gas, tetrakis(triphenylphosphine)palladium(0) (0.05 eq., 17mg, 0.015 mmol) was added, and the reaction mixture was stirred at RTfor 16 h (HPLC control). The mixture was then concentrated under reducedpressure, and the residue was purified by preparative HPLC (column:Gromsil C-18; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10).This gave the title compound as a solid (120 mg, 83% of theory).

LC-MS (Method 5): R_(t)=1.84 min; MS (ESIpos): m/z (%)=494.1 (100)[M+H]⁺; MS (ESIneg): m/z (%)=492.1 (100) [M−H]⁻

¹H-NMR (400 MHz, DMSO-d₆): δ=2.05 (s, 3H), 2.75 (s, 3H), 3.45 (s, 3H),6.70 (s, 1H), 7.75-7.80 (m, 3H), 7.90 (br. s, 1H), 8.15 (br. d, 1H),8.30 (dd, 1H), 8.45 (d, 1H), 12.75 (br. s, 1H).

Example 36A(rac)-Allyl-4-(4-cyano-2-nitrophenyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The reaction was carried out under argon. Allyl acetoacetate (5.94 g,41.5 mmol; 1.0 eq.) was initially charged in THF (117 ml) at RT.Subsequently, 4-cyano-2-nitrobenzaldehyde (10.45 g, 41.5 mmol, purity70%; 1.0 eq.), 1-[3-(trifluoromethyl)phenyl]urea (8.48 g, 41.5 mmol) andtriethyl phosphate (17.7 g) were added. The mixture was stirred underreflux for 16 h. For work-up, initially ice-water was added, and themixture was then taken up in ethyl acetate (400 ml). The organic phasewas dried over solid sodium sulfate, filtered and concentrated underreduced pressure. The crude product was recrystallized from hotwater/isopropanol (2:1, ˜400 ml). The solid obtained was triturated withdiethyl ether (60 ml), once more filtered off with suction, washed witha little diethyl ether and dried under high vacuum. The title compoundwas obtained as a solid (16.63 g, 82% of theory).

LC-MS (Method 8): R_(t)=3.70 min; MS (ESIpos): m/z (%)=487.1 (100)[M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=2.10 (s, 3H), 4.40 (m, 2H), 4.95 (d, 1H),5.05 (d, 1H), 5.70 (m, 1H), 6.15 (d, 1H), 6.05 (d, 1H), 7.70-7.90 (m,4H), 8.10 (br. d, 1H), 8.25 (dd, 1H), 8.45 (d, 1H), 8.55 (d, 1H).

Example 37A(rac)-4-(4-Cyano-2-nitrophenyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

The reaction was carried out under argon. (rac)-Allyl4-(4-cyano-2-nitrophenyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate(15.0 g, 30.8 mmol) and morpholine (1.5 eq., 4.03 g, 46.3 mmol) wereinitially charged in dry THF (300 ml) at RT. The reaction mixture wasdegassed repeatedly (evacuation followed by venting with argon). Underprotective gas, tetrakis(triphenylphosphine)palladium(0) (0.05 eq., 1.78g, 1.54 mmol) was added, and the reaction mixture was stirred at RT for2 h (HPLC control). The mixture was then concentrated, and the residuewas taken up in ethyl acetate (700 ml). The organic phase was washedwith 0.5 N hydrochloric acid (500 ml) and with saturated sodium chloridesolution (300 ml), dried over sodium sulfate, filtered and concentratedunder reduced pressure. The crude product was recrystallized from ethylacetate and dried under high vacuum. The title compound was obtained asa solid (12.87 g, 93% of theory).

¹H-NMR (400 MHz, DMSO-d₆): δ=2.05 (s, 3H), 6.00 (d, 1H), 7.65-7.90 (m,4H), 8.10 (d, 1H), 8.25 (dd, 1H), 8.40 (d, 1H), 8.50 (d, 1H), 12.5 (br.s, 1H).

Example 38A(4R)-4-(4-Cyano-2-nitrophenyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid

(rac)-4-(4-Cyano-2-nitrophenyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (590 g) was separated into the enantiomers by preparative HPLCchromatography on a chiral phase [column: chiral silica gel phase basedon the selector poly(N-methacryloyl-L-leucine-tert-butylamide); columndimensions: 670 mm×40 mm; sample preparation: 100 g of sample dissolvedin 2000 ml of THF; injection volume: 70 ml; mobile phase: ethylacetate/methanol 100:1→1:100; flow rate: 80 ml/min; temperature: 24° C.;detection: 260 nm]. This gave 280 g (95% of theory; 99.6% ee) of the 4Renantiomer.

The enantiomeric excess (ee value) was determined chromatographically[column: chiral silica gel phase based on the selectorpoly(N-methacryloyl-L-leucine-tert-butylamide); column dimensions: 250mm×4.6 mm; mobile phase: ethyl acetate/methanol 10:1; flow rate: 2ml/min; detection: 265 nm; R=1.38 min].

Example 39A(4R)-4-(4-Cyano-2-nitrophenyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide

The reaction was carried out under argon.(4R)-4-(4-Cyano-2-nitrophenyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (6.0 g, 11.4 mmol, purity 85%), DMAP (140 mg, 1.143 mmol; 0.1 eq.),DIEA (1.77 g, 13.7 mmol; 1.2 eq.) and PyBOP (7.14 g, 13.71 mmol; 1.2eq.) were initially charged in dry THF (34 ml) at RT, after briefstirring (15 min), a 0.5 M ammonia solution in THF (5 eq., 57.1 mmol)was added and the mixture was then stirred at RT for 1 h. Ethyl acetate(250 ml) was then added to the reaction mixture. The organic phase waswashed successively with saturated sodium bicarbonate solution, waterand saturated sodium chloride solution, dried over sodium sulfate,filtered and concentrated under reduced pressure. The crude product wassubjected to flash chromatography on silica gel (mobile phase:dichloromethane/methanol 20:1). The title compound was obtained as acolorless solid (5.0 g, 98% of theory).

MS (ESIpos): m/z (%)=446.2 (100) [M+H]⁺.

Example 40A(4R)-4-(4-Cyano-2-nitrophenyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile

The reaction was carried out under argon.(4R)-4-(4-Cyano-2-nitrophenyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide(5.0 g, 10.1 mmol; purity 90%) was initially charged in dry THF (135ml), methoxycarbonylsulfamoyltriethylammonium hydroxide (Burgessreagent; 3.85 g, 16.17 mmol; 1.6 eq.) was added and the mixture was thenstirred at RT for 2 h. Ethyl acetate (300 ml) was then added to thereaction mixture. The organic phase was washed twice with water and oncewith saturated sodium chloride solution, dried over sodium sulfate,filtered and concentrated under reduced pressure. The crude product wasrecrystallized from cyclohexane/ethyl acetate. The crystals obtainedwere dried under high vacuum. The title compound was obtained as a solid(2.8 g, 65% of theory).

¹H-NMR (400 MHz, DMSO-d₆): δ=1.80 (s, 3H), 5.95 (s, 1H), 7.75-8.25 (m,6H), 8.35 (dd, 1H), 8.65 (s, 1H).

Example 41A(4R)-4-(4-Cyano-2-nitrophenyl)-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile

The reaction was carried out under argon.(4R)-4-(4-Cyano-2-nitrophenyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile(5.0 g, 11.7 mmol) was initially charged in absolute THF (500 ml), and a1 M solution of lithium hexamethyldisilazide (LiHMDS) in THF (13.5 ml,13.5 mmol, 1.15 eq.) was added at −78° C. After 30 min of stirring,iodomethane (8.30 g, 58.5 mmol; 5 eq.) in THF was added, and the mixturewas stirred with gradual warming from −78° C. to RT for 16 h. Thereaction mixture was then concentrated under reduced pressure, andinitially 1N hydrochloric acid (14.0 ml), and then MTBE (500 ml) wereadded. The organic phase was washed successively with water (2×),saturated sodium bicarbonate solution, saturated ammonium chloridesolution and saturated sodium chloride solution, dried over sodiumsulfate, filtered and concentrated under reduced pressure. The titlecompound was obtained as a solid (4.3 g, 83% of theory).

LC-MS (Method 4): R_(t)=1.28 min; MS (ESIpos): m/z (%)=442.2 (100)[M+H]⁺; MS (ESIneg): m/z (%)=440.2 (50) [M−H]⁻

¹H-NMR (400 MHz, DMSO-d₆): δ=1.80 (s, 3H), 2.70 (s, 3H), 5.95 (s, 1H),7.75-8.25 (m, 5H), 8.35 (dd, 1H), 8.65 (s, 1H).

Example 42A(4R)-4-(2-Amino-4-cyanophenyl)-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile

Under argon,(4R)-4-(4-cyano-2-nitrophenyl)-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile(6.0 g, 11.3 mmol) was dissolved in methanol (420 ml). 10% palladium onactivated carbon (5.5 g) was then added, and the mixture washydrogenated at RT and atmospheric pressure for 5.5 h (strictlymonitored by HPLC). The reaction mixture was then filtered off overkieselguhr, and the filter residue was washed with methanol (1000 ml).The filtrate was concentrated and the crude product was subjected toflash chromatography on silica gel (mobile phase: ethylacetate/cyclohexane 2:1). The title compound was obtained as a solid(2.28 g, 40% of theory).

LC-MS (Method 9): R_(t)=1.06 min; MS (ESIpos): m/z (%)=412.3 (80)[M+H]⁺; MS (ESIneg): m/z (%)=410.3 (100) [M−H]⁻.

Example 43A5-Cyano-2-{(4S)-5-cyano-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidin-4-yl}benzenesulfonylchloride

Under argon,(4R)-4-(2-amino-4-cyanophenyl)-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile(2.1 g, 5.1 mmol) was initially charged in a 2:1:1 mixture of aceticacid/conc. hydrochloric acid/water (50 ml in total) at −10° C. Asolution of sodium nitrate (371 mg, 5.38 mmol) in water (2 ml) was thenslowly added dropwise, and the mixture was stirred at from −10° C. to−5° C. for 40 min. This solution was then added to 45 ml of a sulfurdioxide-saturated suspension, cooled to −10° C., of copper(I) chloride(101.4 mg, 1.0 mmol) in glacial acetic acid (44 ml). The mixture wasstirred at 0° C. for about 30 min and then at +15° C. for 1 h (reactionmonitored by HPLC and LC-MS). The reaction mixture was then cooled to 0°C. and subsequently added to about 300 ml of ice-cold water using apipette. The precipitate was filtered off and taken up in ethyl acetate(150 ml). The solution was washed twice with saturated sodium chloridesolution, dried over sodium sulfate, filtered and concentrated underreduced pressure. The title compound was obtained as a solid (2.13 g,77% of theory, purity 92%) which was used without further purificationin the subsequent reaction.

LC-MS (Method 4): R_(t)=1.37 min; MS (ESIpos): m/z (%)=495.1 (100)[M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=1.80 (s, 3H), 2.70 (s, 3H), 6.55 (s, 1H),7.75-8.00 (m, 6H), 8.10 (s, 1H).

Example 44A Sodium5-cyano-2-{(4S)-5-cyano-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidin-4-yl}benzenesulfinate

5-Cyano-2-{(4S)-5-cyano-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidin-4-yl}benzenesulfonylchloride (600 mg) was dissolved in THF (4.25 ml). Sodium sulfite (195mg, 1.55 mmol; 1.5 eq.) and sodium bicarbonate (303 mg, 3.61 mmol; 3.5eq.), dissolved in water (1.7 ml), were then added. The mixture wasstirred at RT for 1 h. The reaction solution was then lyophilizeddirectly.

This gave a solid as product (962 mg, 58% of theory, purity 32%) whichwas used without further purification in the subsequent reactions.

LC-MS (Method 9): R_(t)=0.80 min; MS (ESIpos): m/z (%)=461.2 (80)[M+H]⁺; MS (ESIneg): m/z (%)=459.2 (100) [M−H]⁻.

Example 45A(4S)-4-(4-Cyano-2-sulfanylphenyl)-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile

Under argon,5-cyano-2-{(4S)-5-cyano-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidin-4-yl}benzenesulfonylchloride (52 mg, 105 μmol) was dissolved in dichloromethane (10 ml).Triphenylphosphine-polystyrene resin (capacity 1 mmol/g, 315 mg, 315μmol, 3 eq.) was added, and the mixture was shaken for 15 h. Moretriphenylphosphine-polystyrene resin (1 mmol/g, 105 mg, 105 μmol, 1 eq.)was then added, and the mixture was shaken for a further 5 h. Thereaction mixture was then filtered, the filtrate was concentrated underreduced pressure and the residue was dried under high vacuum. The titlecompound was obtained as a solid (90 mg, purity 50%, quant.) which wasused without further purification in the subsequent reactions.

LC-MS (Method 4): R_(t)=1.25 min; MS (ESIpos): m/z (%)=429.1 (100)[M+H]⁺; MS (ESIneg): m/z (%)=427.0 (40) [M−H]⁻

¹H-NMR (400 MHz, DMSO-d₆): δ=1.80 (s, 3H), 2.65 (s, 3H), 3.15 (s, 1H),5.65 (s, 1H), 7.60-7.90 (m, 7H), 8.00 (s, 1H).

Exemplary Embodiments Example 1(rac)-4-{5-Acetyl-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidin-4-yl}-3-(methylsulfonyl)benzonitrile

The reaction was carried out under argon. Triethyl phosphate (251 mg,1.38 mmol) and diphosphorus pentoxide (130 mg, 0.918 mmol) were stirredat 50° C. overnight. The mixture was then diluted with MTBE (5 ml), and4-formyl-3-(methylsulfonyl)benzonitrile (240 mg, 1.15 mmol; Examplel4A), 1-[3-(trifluoromethyl)phenyl]urea (234 mg, 1.15 mmol) and2,4-pentanedione (173 mg, 1.72 mmol) were added. The mixture was stirredunder reflux overnight. For work-up, the solvent was removed underreduced pressure, and the residue was suspended in diethyl ether andthen filtered off with suction. This gave 404 mg (73% of theory) of thetarget compound.

MS (DCI/NH₃): m/z (%)=478.2 (100) [M+H]⁺, 495.2 (28) [M+NH₄]⁺

HPLC (Method 2): R_(t)=4.38 min.

¹H-NMR (400 MHz, DMSO-d₆): δ=2.10 (s, 3H), 2.29 (s, 3H), 3.57 (s, 3H),6.32 (s, 1H), 7.16 (s, 1H), 7.68-7.86 (m, 4H), 8.02 (d, 1H), 8.23 (d,1H), 8.37 (s, 1H).

Example 24-{(4S)-5-Acetyl-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidin-4-yl}-3-(methylsulfonyl)benzonitrile

(rac)-4-{5-Acetyl-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidin-4-yl}-3-(methylsulfonyl)benzonitrile(Example 1, 290 mg) was separated into the enantiomers by preparativeHPLC chromatography on a chiral phase [column: Daicel Chiralpak IA, 250mm×20 mm; sample preparation: the sample was dissolved in 30 ml ofMTBE/methanol/acetonitrile 1:1:1; injection volume: 1.0 ml; mobilephase: MTBE/methanol 1:1; flow rate 15 ml/min; temperature: 30° C.;detection: 220 nm]. This gave 121 mg (83% of theory) of the 4Senantiomer as a colorless amorphous solid.

HPLC (Method 2): R_(t)=4.38 min.

¹H-NMR (400 MHz, DMSO-d₆): δ=2.10 (s, 3H), 2.28 (s, 3H), 3.57 (s, 3H),6.33 (d, 1H), 7.20 (d, 1H), 7.68-7.88 (m, 4H), 8.02 (d, 1H), 8.23 (d,1H), 8.37 (s, 1H).

Optical rotation: [α]²⁰ _(Na)=+18.7° (c=0.56 in DMF).

Example 3

Allyl(rac)-4-[4-cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The reaction was carried out under argon. Triethyl phosphate (22.98 g,126 mmol) and diphosphorus pentoxide (11.94 g, 84.1 mmol) were stirredat 50° C. overnight. The mixture was then diluted with MTBE (450 ml),and 4-formyl-3-(methylsulfonyl)benzonitrile (22.00 g, 105 mmol; Example4A), 1-[3-(trifluoromethyl)phenyl]urea (21.47 g, 105 mmol) and allylacetoacetate (22.42 g, 158 mmol) were added. The mixture was stirredunder reflux overnight. Since the reaction was incomplete, the reactionmixture was concentrated by distillative removal of 350 ml of MTBE. Themixture was then heated under reflux for a further 4 h. For work-up, thesolvent was removed under reduced pressure, and the residue wassuspended in diethyl ether and then filtered off with suction. The solidwas washed with dist. water (350 ml) and then with diethyl ether (50ml). This gave 34.74 g (64% of theory) of the title compound.

LC-MS (Method 4): R_(t)=1.28 min; MS (ESIpos): m/z (%)=520.2 (100)[M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=2.15 (s, 3H), 3.45 (s, 3H), 4.45 (m, 2H),4.95 (d, 1H), 5.05 (d, 1H), 5.65 (m, 1H), 6.40 (d, 1H), 7.20 (d, 1H),7.70 (m, 2H), 7.80 (m, 1H), 7.85 (br. s, 1H), 8.10 (br. d, 1H), 8.25 (d,1H), 8.35 (s, 1H).

Example 4 Allyl(4S)-4-[4-cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate

Allyl(rac)-4-[4-cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate(Example 3, 2.33 g) was separated into the enantiomers by preparativeHPLC chromatography on a chiral phase [column: chiral silica gel phasebased on the selectorpoly(N-methacryloyl-D-leucinedicyclopropylmethylamide); samplepreparation: in each case 1 g of sample dissolved in 70 ml of THF/ethylacetate/isohexane 20:25:25; injection volume: 8 ml; mobile phase:isohexane/isopropanol 1:1; flow rate: 60 ml/min; temperature: 24° C.;detection: 260 nm]. This gave 0.8 g (69% of theory, >99.5% ee) of the 4Senantiomer. The enantiomeric excess (ee value) was determinedchromatographically [column: chiral silica gel phase based on theselector poly(N-methacryloyl-D-leucinedicyclopropylmethylamide), 250mm×4.6 mm; mobile phase: isohexane/ethyl acetate 1:1; flow rate: 2ml/min; detection: 260 nm; R_(t)=1.45 min].

LC-MS (Method 5): R_(t)=2.11 min; MS (ESIpos): m/z (%)=520.1 (100)[M+H]⁺; MS (ESIneg): m/z (%)=475.2 (100), 518.2 (100) [M−H]⁻

¹H-NMR (400 MHz, DMSO-d₆): δ=2.10 (s, 3H), 3.45 (s, 3H), 4.45 (m, 2H),4.95 (d, 1H), 5.05 (d, 1H), 5.65 (m, 1H), 6.40 (d, 1H), 7.20 (d, 1H),7.70 (m, 2H), 7.80 (m, 1H), 7.85 (br. s, 1H), 8.10 (br. d, 1H), 8.25 (d,1H), 8.35 (s, 1H).

Example 5(4S)-4-[4-Cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1.2.3.4-tetrahydropyrimidine-5-carboxamide

The reaction was carried out under argon.(4S)-4-[4-Cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (696 mg, 1.45 mmol; Example 5A) and HATU (2 eq., 1104 mg, 2.9 mmol)were initially charged in dry DMF (35 ml) at 0° C., and after briefstirring (20 min) ammonium chloride (5 eq., 388 mg, 7.26 mmol) and DIEA(7 eq., 1314 mg, 10.16 mmol) were added. The mixture was stirred at RTfor 4 h (monitored by HPLC). The mixture was then concentrated, and theresidue was purified by preparative HPLC (column: Gromsil C-18 10 μm;mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). This gave acolorless amorphous solid (612 mg, 88% of theory).

LC-MS (Method 6): R_(t)=1.94 min; MS (ESIpos): m/z (%)=479.1 (100)[M+H]⁺; MS (ESIneg): m/z (%)=434.1 (100), 477 (40) [M−H]⁻

¹H-NMR (400 MHz, DMSO-d₆): δ=1.80 (s, 3H), 3.40 (s, 3H), 6.35 (s, 1H),7.20 (s, 1H), 7.25 (br. s, 1H), 7.45 (br. s, 1H), 7.65-7.80 (m, 4H),8.10 (d, 1H), 8.30 (s, 1H), 8.35 (d, 1H).

Example 6(4S)-4-[4-Cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile

Method A:

The reaction was carried out under argon.(4S)-4-[4-Cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide(560 mg, 1.17 mmol; Example 5) was initially charged in dry THF (35 ml),methoxycarbonylsulfamoyltriethylammonium hydroxide (Burgess reagent;1115 mg, 4.68 mmol, 4 eq.) was added and the mixture was stirred at RT.After 90 min, HPLC control showed complete conversion. The reactionmixture was concentrated, and the residue was purified by preparativeHPLC (column: Gromsil C-18 10 μm; mobile phase: acetonitrile/water+0.1%TFA 10:90→90:10). The title compound was obtained as a colorlessamorphous solid (470 mg, 87% of theory).

Method B:

(4S)-4-[4-Cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide(10.4 g, 21.7 mmol; Example 5) was, together with triethylamine, (5.63g, 55.6 mmol) dissolved in dry THF (50 ml). Trifluoroacetic anhydride(11.69 g, 55.6 mmol) was added dropwise with slight heat tonality (up to35° C.). After 15 min of stirring, the reaction had gone to completion(monitored by HPLC). Saturated sodium bicarbonate solution (250 ml) wasadded dropwise, and the mixture was extracted twice with ethyl acetate.The combined organic phases were washed with saturated sodium chloridesolution, dried with magnesium sulfate, 30 g of silica gel were addedand the mixture was concentrated on a rotary evaporator. The crudeproduct, which was adsorbed in this manner to silica gel, was purifiedchromatographically on a further 500 g of silica gel (mobile phase:dichloromethane/ethyl acetate 2:1). This gave 6.46 g (65% of theory) ofthe title compound.

m.p.: 258-259° C.

Optical rotation: [α]²⁰ _(Na)=−222.0° (c=0.48 in DMF)

LC-MS (Method 6): R_(t)=2.28 min; MS (ESIpos): m/z (%)=461.1 (100)[M+H]⁺; MS (ESIneg): m/z (%)=352.3 (70), 416.1 (100), 459.2 (70) [M−H]⁻

¹H-NMR (400 MHz, DMSO-d₆): δ=1.80 (s, 3H), 3.40 (s, 3H), 6.45 (s, 1H),7.70-7.85 (m, 3H), 7.95 (br. s, 1H), 8.30-8.40 (m, 4H).

Example 7 tert-Butyl[(6R)-5-cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidine-1(2H)-yl]acetate

The reaction was carried out under argon.(4S)-4-[4-Cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile(290 mg, 630 μmol; Example 6) and sodium hydride (60% in mineral oil,30.2 mg, 756 μmol, 1.2 eq.) were initially charged in THF (12 ml) at 0°C., and after brief stirring (15 min), tert-butyl bromoacetate (175 mg,882 μmol, 1.4 eq.) was added. The reaction mixture was allowed to warmto RT. After 150 min, complete conversion was observed. The reactionmixture was then added to ethyl acetate (100 ml). The organic phase waswashed with saturated sodium chloride solution (2×20 ml), dried oversodium sulfate, filtered and concentrated under reduced pressure. Thecrude product was purified by preparative

HPLC (column: Gromsil C-18 10 μm; mobile phase: acetonitrile/water+0.1%TFA 10:90→90:10). This gave the target compound as a solid (309 mg, 85%of theory).

LC-MS (Method 4): R_(t)=1.38 min; MS (ESIpos): m/z (%)=519.1 (100); MS(ESIneg): m/z (%)=573.4 (100) [M−H]⁻.

General Procedure 1: Synthesis of N-aminocarbonyldihydropyrimidinoneDerivatives (Process A)

4-Nitrophenyl(6S)-5-cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidine-1(2H)-carboxylate(Example 6A, 1 eq.) was dissolved in acetonitrile, and the appropriateamine (3 eq.) was added with stirring. After the reaction had gone tocompletion (monitored by HPLC), the reaction mixture was purifieddirectly by preparative HPLC (column: Kromasil C18, 125 mm×20 mm, 5 μm,100 Å; mobile phase A: water with 0.01% formic acid, mobile phase B:acetonitrile; gradient: 0 min 10% B→2 min 10% B→9 min 90% B→12 min 90%B→12.1 min 10% B→15 min 10% B; flow rate: 0.35 ml/min; UV detection: 254nm). The product fractions were combined and concentrated under reducedpressure.

Example 8(6S)-5-Cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-N-[2-hydroxy-1-(hydroxymethyl)ethyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidine-1(2H)-carboxamide

According to the General Procedure 1, 4-nitrophenyl(6S)-5-cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidine-1(2H)-carboxylate(78.0 mg, 0.125 mmol; Example 6A) was reacted with2-amino-1,3-propanediol (34.1 mg, 0.374 mmol) in acetonitrile (1 ml) togive the target compound (50 mg, 69% of theory).

HPLC (Method 3): R_(t)=4.27 min.

MS (ESIpos): m/z (%)=578.3 (100) [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=1.78 (s, 3H), 3.20-3.57 (m, 5H), 3.50 (s,3H), 4.70 (t, 1H), 4.76 (t, 1H), 7.27 (s, 1H), 7.74-8.23 (m, 5H), 8.29(d, 1H), 8.44 (s, 1H), 8.90-9.02 (br. s, 1H).

Example 9(6S)—N-(2-Amino-2-oxoethyl)-5-cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidine-1(2H)-carboxamide

According to the General Procedure 1, 4-nitrophenyl(6S)-5-cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidine-1(2H)-carboxylate(197 mg, 0.315 mmol; Example 6A) was reacted with glycinamidehydrochloride (104 mg, 0.945 mmol) and N,N-diisopropylethylamine (122mg, 0.945 mmol) in acetonitrile (2.5 ml) to give the target compound (72mg, 39% of theory).

HPLC (Method 2): R=4.24 min.

MS (ESIpos): m/z (%)=561.3 (100) [M+H]⁺, 583.2 (50) [M+Na]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=1.80 (s, 3H), 3.49 (s, 3H), 3.67 (dd, 2H),7.12 (s, 1H), 7.26 (s, 1H), 7.36 (s, 1H), 7.72-8.23 (m, 5H), 8.29 (d,1H), 8.43 (s, 1H), 9.14 (br. s, 1H).

Example 10(6S)-5-Cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-N-(2-hydroxyethyl)-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidine-1(2H)-carboxamide

According to the General Procedure 1, 4-nitrophenyl(6S)-5-cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidine-1(2H)-carboxylate(80.0 mg, 0.128 mmol; Example 6A) was reacted with 2-aminoethanol (23.4mg, 0.384 mmol) in acetonitrile (1 ml) to give the target compound (27mg, 39% of theory).

HPLC (Method 2): R_(t)=4.39 min.

MS (ESIpos): m/z (%)=548.2 (100) [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=1.78 (s, 3H), 3.03-3.45 (m, 4H), 3.50 (s,3H), 4.74 (m, 1H), 7.26 (s, 1H), 7.74-8.22 (m, 5H), 8.29 (d, 1H), 8.43(s, 1H), 8.94 (br. s, 1H).

Example 11(6S)-5-Cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-4-methyl-N-morpholin-4-yl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidine-1(2H)-carboxamide

According to the General Procedure 1, 4-nitrophenyl(6S)-5-cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidine-1(2H)-carboxylate(78.0 mg, 0.125 mmol; Example 6A) was reacted with N-aminomorpholine(38.2 mg, 0.374 mmol) in acetonitrile (1 ml) to give the target compound(46 mg, 61% of theory).

HPLC (Method 3): R_(t)=4.49 min.

MS (ESIpos): m/z (%)=589.3 (100) [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=1.80 (s, 3H), 2.53-2.72 (m, 4H), 3.47-3.56(m, 4H), 3.50 (s, 3H), 7.11 (s, 1H), 7.74-8.21 (m, 5H), 8.32 (d, 1H),8.43 (s, 1H), 9.63 (s, 1H).

Example 12(6S)-5-Cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-N′,N′-bis(2-hydroxyethyl)-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidine-1(2H)-carbohydrazide

According to the General Procedure 1, 4-nitrophenyl(6S)-5-cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidine-1(2H)-carboxylate(78.0 mg, 0.125 mmol; Example 6A) was reacted with2,2′-hydrazin-1,1-diyldiethanol (45.0 mg, 0.374 mmol) in acetonitrile (1ml) to give the target compound (40 mg, 51% of theory).

HPLC (Method 3): R_(t)=4.23 min.

MS (ESIpos): m/z (%)=607.3 (100) [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=1.80 (s, 3H), 2.70 (t, 4H), 3.20 (m, 4H),3.46 (s, 3H), 4.15 (t, 2H), 7.11 (s, 1H), 7.74-8.37 (m, 6H), 8.44 (s,1H), 9.60 (s, 1H).

Example 13(6S)-5-Cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-N-(2-hydroxy-1,1-dimethylethyl)-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidine-1(2H)-carboxamide

According to the General Procedure 1, 4-nitrophenyl(6S)-5-cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidine-1(2H)-carboxylate(75.0 mg, 0.120 mmol; Example 6A) was reacted with2-amino-2-methylpropanol (32.1 mg, 0.360 mmol) in acetonitrile (0.96 ml)to give the target compound (51 mg, 74% of theory).

HPLC (Method 2): R_(t)=4.65 min.

MS (ESIpos): m/z (%)=576.2 (100) [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=1.02 (s, 3H), 1.13 (s, 3H), 1.78 (s, 3H),3.13-3.28 (m, 2H), 3.51 (s, 3H), 4.98 (t, 1H), 7.26 (s, 1H), 7.74-8.23(m, 5H), 8.30 (d, 1H), 8.45 (s, 1H), 8.98 (br. s, 1H).

Example 14(6S)-5-Cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-N-[2-(2-hydroxyethoxy)ethyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidine-1(2H)-carboxamide

According to the General Procedure 1, 4-nitrophenyl(6S)-5-cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidine-1(2H)-carboxylate(46.5 mg, 0.074 mmol; Example 6A) was reacted with2-(2-aminoethoxy)ethanol (23.4 mg, 0.223 mmol) in acetonitrile (1 ml) togive the target compound (30 mg, 68% of theory).

HPLC (Method 2): R_(t)=4.39 min.

MS (ESIpos): m/z (%)=592.2 (100) [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=1.78 (s, 3H), 3.16-3.25 (m, 2H), 3.26-3.43(m, 6H), 3.50 (s, 3H), 4.52 (m, 1H), 7.25 (s, 1H), 7.74-8.23 (m, 5H),8.29 (d, 1H), 8.44 (s, 1H), 8.90 (br. s, 1H).

Example 15(6S)-5-Cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-N-cyclopropyl-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidine-1(2H)-carboxamide

According to the General Procedure 1, 4-nitrophenyl(6S)-5-cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidine-1(2H)-carboxylate(80.0 mg, 0.128 mmol; Example 6A) was reacted with cyclopropylamine(21.9 mg, 0.384 mmol) in acetonitrile (1 ml) to give the target compound(45 mg, 65% of theory).

HPLC (Method 3): R_(t)=4.83 min.

MS (ESIpos): m/z (%)=544.2 (100) [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=0.28-0.65 (m, 4H), 1.78 (s, 3H), 2.51-2.61(m, 1H), 3.52 (s, 3H), 7.21 (s, 1H), 7.74-8.19 (m, 5H), 8.30 (d, 1H),8.44 (s, 1H), 8.72 (br. s, 1H).

Example 16(6S)-5-Cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-N-(1,1-dioxidotetrahydrothiophen-3-yl)-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidine-1(2H)-carboxamide

According to the General Procedure 1, 4-nitrophenyl(6S)-5-cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidine-1(2H)-carboxylate(78.0 mg, 0.125 mmol; Example 6A) was reacted withtetrahydrothiophen-3-amine 1,1-dioxide (50.6 mg, 0.374 mmol) inacetonitrile (1 ml) to give the target compound (52 mg, 66% of theory).

HPLC (Method 3): R_(t)=4.55 min.

MS (ESIpos): m/z (%)=622.3 (70) [M+H]⁺, 639.3 (38) [M+NH₄]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=1.79 (s, 3H), 1.92-2.37 (m, 2H), 2.90-3.35(m, 4H), 3.50 (s, 3H), 4.39 (m, 1H), 7.24 (s, 1H), 7.72-8.18 (m, 5H),8.29 (d, 1H), 8.44 (s, 1H), 9.13 (br. s, 1H).

Example 17(6S)-5-Cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-N-(2-methoxyethyl)-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidine-1(2H)-carboxamide

According to the General Procedure 1, 4-nitrophenyl(6S)-5-cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidine-1(2H)-carboxylate(78.0 mg, 0.125 mmol; Example 6A) was reacted with 2-methoxyethylamine(28.1 mg, 0.374 mmol) in acetonitrile (1 ml) to give the target compound(55 mg, 78% of theory).

HPLC (Method 3): R_(t)=4.72 min.

MS (ESIpos): m/z (%)=562.3 (100) [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=1.78 (s, 3H), 3.15 (s, 3H), 3.17-3.32 (m,4H), 3.50 (s, 3H), 7.25 (s, 1H), 7.74-8.23 (m, 5H), 8.29 (d, 1H), 8.43(s, 1H), 8.90 (br. s, 1H).

Example 18(4S)-4-[4-Cyano-2-(methylsulfonyl)phenyl]-3-{[(3S)-3-hydroxypyrrolidin-1-yl]carbonyl}-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile

According to the General Procedure 1, 4-nitrophenyl(6S)-5-cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidine-1(2H)-carboxylate(135 mg, 0.216 mmol; Example 6A) was reacted with (S)-(−)-3-pyrrolidinol(56.4 mg, 0.647 mmol) in acetonitrile (1.7 ml) to give the targetcompound (48 mg, 38% of theory).

HPLC (Method 2): R_(t)=4.21 min.

MS (DCI/NH₃): m/z=574 [M+H]⁺, 591.3 [M+NH₄]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=1.59-1.95 (m, 2H), 1.83 (s, 3H), 2.86-3.36(m, 2H), 3.44-3.72 (m, 2H), 3.48 (s, 3H), 4.19 (m, 1H), 4.87 and 5.08(in each case d, 1H), 6.82 (s, 1H), 7.73-8.43 (m, 7H).

Example 19(4S)-4-[4-Cyano-2-(methylsulfonyl)phenyl]-3-{[(3R)-3-hydroxypyrrolidin-1-yl]carbonyl}-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile

According to the General Procedure 1, 4-nitrophenyl(6S)-5-cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidine-1(2H)-carboxylate(135 mg, 0.216 mmol; Example 6A) was reacted with (R)-(+)-3-pyrrolidinol(56.4 mg, 0.647 mmol) in acetonitrile (1.7 ml) to give the targetcompound (92 mg, 74% of theory).

HPLC (Method 2): R_(t)=4.21 min.

MS (ESI): m/z (%)=ESI⁺574.2 (10) [M+H]⁺, ESI⁻ 618.1 (100) [M−H+HCOOH]⁻

¹H-NMR (400 MHz, DMSO-d₆): δ=1.63-1.88 (m, 2H), 1.82 (s, 3H), 2.95-3.23(m, 2H), 3.34-3.84 (m, 2H), 3.49 (s, 3H), 4.17 and 4.26 (in each casebr. s, 1H), 4.86 and 4.91 (in each case br. s, 1H), 6.84 (s, 1H),7.73-8.25 (m, 6H), 8.34-8.41 (m, 1H).

Example 20(4S)-4-[4-Cyano-2-(methylsulfonyl)phenyl]-3-{[4-(2-hydroxyethyl)piperazin-1-yl]carbonyl}-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile

According to the General Procedure 1, 4-nitrophenyl(6S)-5-cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidine-1(2H)-carboxylate(78 mg, 0.125 mmol; Example 6A) was reacted withN-(2-hydroxyethyl)piperazine (48.7 mg, 0.374 mmol) in acetonitrile (1.0ml) to give the target compound (68 mg, 85% of theory).

HPLC (Method 3): R_(t)=4.18 min.

MS (ESIpos): m/z (%)=617.3 (100) [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=1.81 (s, 3H), 2.03-2.73 (m, 4H), 2.94-3.87(m, 11H, including t at 3.47, s at 3.51), 4.41 (br. s, 1H), 6.83 (s,1H), 6.91-8.52 (m, 7H).

Example 212-[(6S)-5-Cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidin-1(2H)-yl]aceticacid

The reaction was carried out under argon. tert-Butyl[(6R)-5-cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidin-1(2H)-yl]acetate(350 mg, 609 μmol; Example 7) was initially charged in dichloromethane(60 ml), and trifluoroacetic acid (20 ml) was added. The mixture wasstirred at RT for 90 min. The volatile components were then removed on arotary evaporator. The residue was taken up in toluene (50 ml) and againconcentrated under reduced pressure. This procedure was repeated oncemore. The crude product was purified by preparative HPLC (column:Gromsil C-18 10 μm; mobile phase: acetonitrile/water+0.1% TFA10:90→90:10). The title compound was obtained as a colorless solid (290mg, 92% of theory).

LC-MS (Method 4): R_(t)=1.11 min; MS (ESIpos): m/z (%)=519.0 (100)[M+H]⁺; MS (ESIneg): m/z (%)=352.1 (100), 415.9 (70), 517.0 (50) [M−H]⁻.

Example 222-[(6S)-5-Cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidin-1(2H)-yl]acetamide

The reaction was carried out under argon.2-[(6S)-5-Cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidin-1(2H)-yl]aceticacid (90 mg, 174 μmol; Example 21) was initially charged in DMF (3 ml),HATU (330 mg, 868 μmol, 5 eq.) was added at 0° C. and the mixture wasstirred for 20 min. Ammonium chloride (18.1 mg, 340 μmol, 5 eq.) andN,N-diisopropylethylamine (224 mg, 1736 μmol, 10 eq.) were then added,and the mixture was stirred at RT until complete conversion had beenachieved (after a number of hours; HPLC control). The reaction mixturewas then concentrated under reduced pressure, and the crude product waspurified by preparative HPLC (Column: Gromsil C-18 10 μm; mobile phase:acetonitrile/water+0.1% TFA 10:90→90:10). This gave the title compoundas a colorless solid (85 mg, 94% of theory).

LC-MS (Method 4): R_(t)=1.07 min; MS (ESIpos): m/z (%)=501.1 (70), 518.1(100) [M+H]⁺; MS (ESIneg): m/z (%)=516.7 (80) [M−H]⁻

¹H-NMR (400 MHz, DMSO-d₆): δ=1.85 (s, 3H), 3.15 (br. d, 1H), 3.40 (s,3H), 4.05 (d, 1H), 6.50 (s, 1H), 7.10 (s, 1H), 7.40 (s, 1H), 7.65-8.05(m, 4H), 8.40 (m, 3H).

Example 232-[(6S)-5-Cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidin-1(2H)-yl]-N-(2-hydroxyethyl)acetamide

The reaction was carried out under argon.2-[(6S)-5-Cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidin-1(2H)-yl]aceticacid (45 mg, 87 μmol; Example 21) was initially charged in DMF (1.5 ml),HATU (165 mg, 434 μmol, 5 eq.) was added at 0° C. and the mixture wasstirred for 20 min. 2-Aminoethanol (26.5 mg, 434 μmol, 5 eq.) andN,N-diisopropylethylamine (56 mg, 434 μmol, 5 eq.) were then added, andthe mixture was stirred at RT for 16 h until complete conversion hadbeen achieved (HPLC control). The reaction mixture was then concentratedunder reduced pressure, and the crude product was purified bypreparative HPLC (column: Gromsil C-18 10 μm; mobile phase:acetonitrile/water+0.1% TFA 10:90→90:10). This gave the title compoundas a colorless solid (40 mg, 82% of theory).

LC-MS (Method 6): R_(t)=2.05 min; MS (ESIpos): m/z (%)=562.1 (100)[M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=1.85 (s, 3H), 3.05 (m, 2H), 3.20 (d, 1H),3.35 (m, 2H), 3.40 (s, 3H), 4.05 (d, 1H), 6.50 (s, 1H), 7.65-8.10 (m,5H), 8.30-8.45 (m, 3H).

Example 24

(4S)-4-[4-Cyano-2-(methylsulfonyl)phenyl]-3-{2-[4-(2-hydroxyethyl)piperidin-1-yl]-2-oxoethyl}-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile

The reaction was carried out under argon.2-[(6S)-5-Cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidin-1(2H)-yl]aceticacid (45 mg, 87 μmol; Example 21) was initially charged in DMF (1.5 ml),HATU (165 mg, 434 μmol, 5 eq.) was added at 0° C. and the mixture wasstirred for 20 min. 4-Piperidinethanol (33.6 mg, 260 μmol, 3 eq.) andN,N-diisopropylethylamine (56 mg, 434 μmol, 5 eq.) were then added, andthe mixture was stirred at RT for 16 h until complete conversion hadbeen achieved (HPLC control). The reaction mixture was then concentratedunder reduced pressure, and the crude product was purified bypreparative HPLC (column: Gromsil C-18 10 μm; mobile phase:acetonitrile/water+0.1% TFA 10:90→90:10). This gave the title compoundas a colorless solid (26 mg, 48% of theory, purity about 80%).

LC-MS (Method 6): R_(t)=2.22 min; MS (ESIpos): m/z (%)=630.2 (100)[M+H]⁺.

Example 25(4S)-4-[4-Cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-3-[2-oxo-2-(3-oxopiperazin-1-yl)ethyl]-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile

The reaction was carried out under argon.2-[(6S)-5-Cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidin-1(2H)-yl]aceticacid (50 mg, 96 μmol; Example 21) was initially charged in DMF (2 ml),HATU (183 mg, 482 μmol, 5 eq.) was added at 0° C. and the mixture wasstirred for 20 min. 2-Oxopiperazine (48.3 mg, 482 μmol, 5 eq.) andN,N-diisopropylethylamine (62 mg, 482 μmol, 5 eq.) were then added, andthe mixture was stirred at RT for 30 min until complete conversion hadbeen achieved (HPLC control). The reaction mixture was then concentratedunder reduced pressure and the crude product was purified by preparativeHPLC (column: Gromsil C-18 10 μm; mobile phase: acetonitrile/water+0.1%TFA 10:90→90:10). This gave the title compound as a colorless solid (32mg, 55% of theory).

LC-MS (Method 6): R_(t)=2.05 min; MS (ESIpos): m/z (%)=601.2 (100)[M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=1.85 (s, 3H), 3.05 (m, 2H), 3.20-3.65 (m,3H), 3.40 (s, 3H), 3.80-4.00 (m, 2H), 4.45 (t, 1H), 6.35 (s, 1H),7.65-8.10 (m, 5H), 8.30-8.45 (m, 3H).

Example 26(4S)-4-[4-Cyano-2-(methylsulfonyl)phenyl]-3-{2-[4-hydroxypiperidin-1-yl]-2-oxoethyl}-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile

The reaction was carried out under argon.2-[(6S)-5-Cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidin-1(2H)-yl]aceticacid (45 mg, 87 μmol; Example 21) was initially charged in DMF (1.5 ml),HATU (165 mg, 434 μmol, 5 eq.) was added at 0° C. and the mixture wasstirred for 20 min. 4-Hydroxypiperidine (43.9 mg, 434 μmol, 5 eq.) andN,N-diisopropylethylamine (56 mg, 434 μmol, 5 eq.) were then added, andthe mixture was stirred at RT for 16 h until complete conversion hadbeen achieved (HPLC control). The reaction mixture was then concentratedunder reduced pressure, and the crude product was purified bypreparative HPLC (column: Gromsil C-18 10 μm; mobile phase:acetonitrile/water+0.1% TFA 10:90→90:10). This gave the title compoundas a colorless solid (51 mg, 98% of theory).

LC-MS (Method 6): R_(t)=2.13 min; MS (ESIpos): m/z (%)=602.1 (100)[M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=1.20 (m, 2H), 1.65 (m, 2H), 1.85 (s, 3H),2.95 (m, 2H), 3.15 (m, 1H), 3.40 (s, 3H), 3.55-3.70 (m, 2H), 3.95 (m,1H), 4.45 (m, 1H), 6.35 (s, 1H), 7.65-8.10 (m, 4H), 8.30-8.45 (m, 3H).

Example 27(4S)-4-[4-Cyano-2-(methylsulfonyl)phenyl]-6-methyl-3-(methylsulfonyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile

The reaction was carried out under argon.(4S)-4-[4-Cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile(69.1 mg, 150 μmol; Example 6) was initially charged in THF (2 ml), andsodium hydride (60% in mineral oil; 7.2 mg, 180 μmol) was added at 0° C.The mixture was warmed to RT and stirred for 20 min. A solution ofmethanesulfonyl chloride (20.6 mg, 180 μmol, 1.2 eq.) in THF (1 ml) wasthen slowly added dropwise. After a reaction time of 16 h, moremethanesulfonyl chloride (6.7 mg, 60 μmol, 0.4 eq.) was added, and themixture was again stirred at RT for 60 min. The reaction mixture wasthen concentrated, and the crude product was purified by preparativeHPLC (column: Gromsil C-18 10 μm; mobile phase: acetonitrile/water+0.1%TFA 10:90→80:20). This gave the title compound as a colorless solid (47mg, 58% of theory).

LC-MS (Method 4): R_(t)=1.22 min; MS (ESIpos): m/z (%)=539.0 (30)[M+H]⁺; MS (ESIneg): m/z (%)=353.3 (100), 415.9 (50), 457.2 (80), 535.6(100) [M−H]⁻

¹H-NMR (400 MHz, DMSO-d₆): δ=1.80 (s, 3H), −3.40 (2s, 6H), 7.30 (s, 1H),7.75-8.35 (m, 6H), 8.55 (s, 1H).

Example 28(4S)-4-[4-Cyano-2-(methylsulfonyl)phenyl]-6-methyl-3-(isopropylsulfonyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile

Analogously to the preparation of Example 27,(4S)-4-[4-cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile(100 mg, 217 μmol; Example 6), sodium hydride (60%, 11.2 mg, 282 μmol)and 2-propanesulfonyl chloride (40.3 mg, 282 μmol) were reacted with oneanother for 16 h. This gave the title compound as a colorless solid (88mg, 72% of theory).

LC-MS (Method 5): R_(t)=2.15 min; MS (ESIpos): m/z (%)=567.2 (100)[M+H]⁺; MS (ESIneg): m/z (%)=565.2 (100) [M−H]⁻

¹H-NMR (400 MHz, DMSO-d₆): δ=1.10 (d, 3H), 1.35 (d, 3H), 1.80 (s, 3H),3.40 (s, 3H), 4.05 (m, 1H), 7.25 (s, 1H), 7.75-8.25 (m, 6H), 8.55 (s,1H).

Example 29(4S)-4-[4-Cyano-2-(methylsulfonyl)phenyl]-6-methyl-3-{[2-(trifluoromethoxy)phenyl]sulfonyl}-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile

Analogously to the preparation of Example 27,(4S)-4-[4-cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile(100 mg, 217 μmol; Example 6), sodium hydride (60%, 11.2 mg, 282 μmol)and [2-(trifluoromethoxy)phenyl]sulfonyl chloride (73.6 mg, 282 μmol)were reacted with one another for 16 h. This gave the title compound asa colorless solid (115 mg, 77% of theory).

LC-MS (Method 4): R_(t)=1.39 min; MS (ESIpos): m/z (%)=685.0 (40)[M+H]⁺; MS (ESIneg): m/z (%)=457.5 (100), 683.6 (80) [M−H]

¹H-NMR (400 MHz, DMSO-d₆): δ=1.80 (s, 3H), 3.45 (s, 3H), 7.35-8.40 (m,11H), 8.60 (s, 1H).

Example 30(4S)-4-[4-Cyano-2-(methylsulfonyl)phenyl]-6-methyl-3-((chloromethyl)sulfonyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile

Analogously to the preparation of Example 27,(4S)-4-[4-cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile(100 mg, 217 μmol; Example 6), sodium hydride (60%, 11.3 mg, 282 μmol)and chloromethanesulfonyl chloride (42 mg, 282 μmol) were reacted withone another for 3 h. This gave the title compound as a colorless solid(86 mg, 69% of theory).

LC-MS (Method 5): R_(t)=2.11 min; MS (ESIpos): m/z (%)=573.1 (100)[M+H]⁺; MS (ESIneg): m/z (%)=571.1 (100) [M−H]⁻

¹H-NMR (400 MHz, DMSO-d₆): δ=1.85 (s, 3H), 3.45 (s, 3H), 5.45 (d, 1H),5.55 (d, 1H), 7.35 (s, 1H), 7.80-8.35 (m, 6H), 8.60 (s, 1H).

Example 31(4S)-4-[4-Cyano-2-(methylsulfonyl)phenyl]-6-methyl-3-(ethylsulfonyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile

Analogously to the preparation of Example 27,(4S)-4-[4-cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile(100 mg, 217 μmol; Example 6), sodium hydride (60%, 11.2 mg, 282 μmol)and ethanesulfonyl chloride (36 mg, 282 μmol) were reacted with oneanother for 3 h. This gave the title compound as a colorless solid (99mg, 83% of theory).

LC-MS (Method 5): R_(t)=2.06 min; MS (ESIpos): m/z (%)=553.1 (100)[M+H]⁺; MS (ESIneg): m/z (%)=416.2 (50), 551.2 (90) [M−H]⁻

¹H-NMR (400 MHz, DMSO-d₆): δ=1.15 (t, 3H), 1.80 (s, 3H), 3.40 (s, 3H),3.55 (m, 1H), 3.75 (m, 1H), 7.30 (s, 1H), 7.70-8.35 (m, 6H), 8.55 (s,1H).

Example 32(4S)-4-[4-Cyano-2-(methylsulfonyl)phenyl]-6-methyl-3-(cyclopropylsulfonyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile

Analogously to the preparation of Example 27,(4S)-4-[4-cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile(100 mg, 217 μmol; Example 6), sodium hydride (60%, 11.2 mg, 282 μmol)and cyclopropylsulfonyl chloride (39.7 mg, 282 μmol) were reacted withone another for 16 h. This gave the title compound as a colorless solid(57 mg, 47% of theory).

LC-MS (Method 5): R_(t)=2.07 min; MS (ESIpos): m/z (%)=565.1 (100)[M+H]⁺; MS (ESIneg): m/z (%)=416.2 (80), 563.2 (80) [M−H]⁻

¹H-NMR (400 MHz, DMSO-d₆): δ=0.30 (br. m, 1H), 0.85 (br. m, 1H), 1.15(m, 2H), 1.80 (s, 3H), 3.10 (m, 1H), 3.40 (s, 3H), 7.30 (s, 1H),7.75-8.35 (m, 6H), 8.55 (s, 1H).

Example 33(4S)-4-[4-Cyano-2-(methylsulfonyl)phenyl]-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile

Method A:

The reaction was carried out under argon.(4S)-4-[4-Cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile(75 mg, 163 μmol; Example 6) was initially charged in THF (2 ml) andsodium hydride (60% in mineral oil; 9.2 mg, 228 μmol) was added. After20 min of stirring, iodomethane (32.4 mg, 14.2 μl, 228 μmol) was added,and the mixture was stirred at RT for a further 120 min. The reactionmixture was then purified by preparative HPLC (column: Kromasil-100A,C-18 5 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→80:20). Thisgave the title compound as a colorless solid (18 mg, 23% of theory).

Method B:

The reaction was carried out under argon.(4S)-4-[4-Cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile(460.4 mg, 1 mmol; Example 6) was initially charged in absolute THF (10ml), and at −78° C. a 1 M solution of lithium hexamethyldisilazide(LiHMDS) in THF (1 ml; 1 eq.) was added. After 20 min of stirring,iodomethane (710 mg; 5 eq.) was added, and the mixture was stirred withgradual warming from −78° C. to RT for 60 h. The reaction mixture wasthen purified directly by preparative HPLC (column: Gromsil, C-18 10 μm;mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). This gave thetitle compound as a colorless solid (454 mg, 96% of theory).

Method C:

Sodium5-cyano-2-{(4S)-5-cyano-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidin-4-yl}benzenesulfinate(150 mg, 65 μmol; purity about 21%) was suspended under argon in apressure-proof glass tube in DMF (1 ml). Molecular sieve (4 Å, 20 mg)and methyl iodide (82 μl, 1.3 mmol; 20 eq.) were added. The sealed tubewas heated at 115° C. for 15 h. The reaction mixture was then filtered,and the filtrate was concentrated under reduced pressure. The residuewas purified by preparative HPLC (Gromsil C18 column; mobile phase:acetonitrile/water+0.1% TFA). Lyophilization gave the title compound asa solid (29.4 mg, 95% of theory).

LC-MS (Method 4): R_(t)=1.21 min; MS (ESIpos): m/z (%)=475.0 (100)[M+H]⁺; MS (ESIneg): m/z (%)=473.2 (100) [M−H]⁻

¹H-NMR (400 MHz, DMSO-d₆): δ=1.80 (s, 3H), 2.65 (s, 3H), 3.40 (s, 3H),6.45 (s, 1H), 7.65-8.40 (m, 6H), 8.45 (s, 1H).

Example 34(rac)-4-{6-Methyl-2,5-dioxo-1-[3-(trifluoromethyl)phenyl]-2,3,4,5,6,7-hexahydro-1H-pyrrolo[3,4-d]pyrimidin-4-yl}-3-(methylsulfonyl)benzonitrile

Under an argon protective gas atmosphere, (rac)-2,3-dibromopropyl6-(bromomethyl)-4-[4-cyano-2-(methylsulfonyl)phenyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate(758.2 mg, 1.0 mmol; Example 7A) was mixed with a 1 M solution ofmethylamine in THF (20 ml, 20.0 mmol, 20 eq.), and the mixture wasstirred at RT for 30 min. The reaction mixture was then concentratedunder reduced pressure, and the crude product was purified bypreparative HPLC (column: Gromsil C-18 10 μm; mobile phase:acetonitrile/water+0.1% TFA 10:90→90:10). This gave the title compoundas a colorless solid (328 mg, 67% of theory).

LC-MS (Method 5): R_(t)=1.61 min; MS (ESIpos): m/z (%)=491.1 (100)[M+H]⁺; MS (ESIneg): m/z (%)=489.1 (100) [M−H]⁻

¹H-NMR (400 MHz, DMSO-d₆): δ=2.65 (s, 3H), 3.55 (s, 3H), 3.85 (m, 2H),6.65 (s, 1H), 7.70-7.85 (m, 3H), 8.00 (s, 1H), 8.10 (s, 1H), 8.15 (d,1H), 8.25 (dd, 1H), 8.30 (s, 1H).

Example 354-{(4S)-6-Methyl-2,5-dioxo-1-[3-(trifluoromethyl)phenyl]-2,3,4,5,6,7-hexahydro-1H-pyrrolo[3,4-d]pyrimidin-4-yl}-3-(methylsulfonyl)benzonitrile

(rac)-4-{6-Methyl-2,5-dioxo-1-[3-(trifluoromethyl)phenyl]-2,3,4,5,6,7-hexahydro-1H-pyrrolo[3,4-d]pyrimidin-4-yl}-3-(methylsulfonyl)benzonitrile(Example 34, 190 mg) was separated into the enantiomers by preparativeHPLC chromatography on a chiral phase [column: Daicel Chiralpak IC, 5μm, 250 mm×20 mm; sample preparation: the sample was dissolved in 70 mlof methanol/acetonitrile/MTBE 25:10:35; injection volume: 1 ml; mobilephase: MTBE/methanol 75:25 (0-7 min); flow rate: 15 ml/min; temperature:30° C.; detection: 220 nm]. This gave 97 mg (100% of theory, >99.0% ee)of the 4S enantiomer. The enantiomeric excess (ee value) was determinedchromatographically [column: Daicel Chiralpak IC, 5 μm, 250 mm×4.6 mm;mobile phase: MTBE/methanol 75:25; flow rate: 1 ml/min; temperature: 25°C.; detection: 220 nm; R=6.62 min].

LC-MS (Method 5): R_(t)=1.59 min; MS (ESIpos): m/z (%)=491.1 (100)[M+H]⁺; MS (ESIneg): m/z (%)=446.2 (70), 489.2 (100) [M−H]⁻.

Example 364-{(4S)-6-Methyl-3-(methylsulfonyl)-2,5-dioxo-1-[3-(trifluoromethyl)phenyl]-2,3,4,5,6,7-hexahydro-1H-pyrrolo[3,4-d]pyrimidin-4-yl}-3-(methylsulfonyl)benzonitrile

Analogously to the preparation of Example 27,4-{(4S)-6-methyl-2,5-dioxo-1-[3-(trifluoromethyl)phenyl]-2,3,4,5,6,7-hexahydro-1H-pyrrolo[3,4-d]pyrimidin-4-yl}-3-(methylsulfonyl)benzonitrile(20 mg, 41 μmol; Example 35), sodium hydride (60%, 2.3 mg, 57 μmol) andmethanesulfonyl chloride (6.5 mg, 57 μmol) were reacted with one anotherfor 2 h. The title compound was obtained as a colorless solid (1.7 mg,7% of theory). In addition, 6.4 mg (32% of theory) of the startingmaterial were recovered.

LC-MS (Method 4): R_(t)=1.10 min; MS (ESIpos): m/z (%)=569.0 (100)[M+H]⁺; MS (ESIneg): m/z (%)=568.4 (100) [M−H]⁻.

Example 37(rac)-2-{4-[4-Cyano-2-(methylsulfonyl)phenyl]-6-methyl-2,5-dioxo-1-[3-(trifluoromethyl)phenyl]-1,2,4,5,6,7-hexahydro-3H-pyrrolo[3,4-d]pyrimidin-3-yl}acetamide

The title compound was obtained from(rac)-4-{6-methyl-2,5-dioxo-1-[3-(trifluoromethyl)phenyl]-2,3,4,5,6,7-hexahydro-1H-pyrrolo[3,4-d]pyrimidin-4-yl}-3-(methylsulfonyl)benzonitrile(Example 34) analogously to the multi-step preparation of2-[(6S)-5-cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidin-1(2H)-yl]acetamide(Example 22) from(4S)-4-[4-cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(tri-fluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile(Example 6).

LC-MS (Method 5): R_(t)=1.44 min; MS (ESIpos): m/z (%)=548.1 (100)[M+H]⁺; MS (ESIneg): m/z (%)=546.1 (100) [M−H]⁻

¹H-NMR (400 MHz, DMSO-d₆): δ=2.70 (s, 3H), 3.30 (d, 1H), 3.90 (m, 2H),3.95 (d, 1H), 6.55 (s, 1H), 6.95 (s, 1H), 7.30 (s, 1H), 7.75-7.85 (m,3H), 8.00 (s, 1H), 8.20-8.30 (m, 2H), 8.35 (s, 1H) [a methyl group isobscured by the solvent peak].

Example 38(rac)-4-[4-Cyano-2-(methylsulfonyl)phenyl]-N-(2-hydroxyethyl)-6-methyl-2,5-dioxo-1-[3-(trifluoromethyl)phenyl]-1,2,4,5,6,7-hexahydro-3H-pyrrolo[3,4-d]pyrimidine-3-carboxamide

The title compound was prepared from(rac)-4-{6-methyl-2,5-dioxo-1-[3-(trifluoromethyl)phenyl]-2,3,4,5,6,7-hexahydro-1H-pyrrolo[3,4-d]pyrimidin-4-yl}-3-(methylsulfonyl)benzonitrile(Example 34) analogously to the multi-step preparation of(6S)-5-cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-N-(2-hydroxyethyl)-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidine-1(2H)-carboxamide(Example 10) from(4S)-4-[4-cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile(Example 6).

LC-MS (Method 5): R_(t)=1.56 min; MS (ESIpos): m/z (%)=578.1 (100)[M+H]⁺; MS (ESIneg): m/z (%)=489.2 (100), 576 (70) [M−H]⁻.

Example 39 Allyl(rac)-4-[4-cyano-2-(methylsulfanyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The reaction was carried out under argon. Triethyl phosphate (1.46 g,8.04 mmol) and diphosphorus pentoxide (761 mg, 5.36 mmol) were stirredat 50° C. overnight. The mixture was then diluted with MTBE (27 ml), and4-formyl-3-(methylsulfanyl)benzonitrile (1.18 g, 6.70 mmol; Example 9A),1-[3-(trifluoromethyl)phenyl]urea (1.37 g, 6.70 mmol) and allylacetoacetate (1.43 g, 10.1 mmol) were added. The mixture was stirredunder reflux overnight. For work-up, the solvent was removed underreduced pressure and the residue was suspended in diethyl ether and thenfiltered of with suction. This gave 978 mg (19% of theory) of the titlecompound.

LC-MS (Method 4): R_(t)=1.37 min; MS (ESIpos): m/z (%)=488.3 (100)[M+H]⁺; MS (ESIneg): m/z (%)=486.2 (65) [M−H]⁻.

Example 40(4S)-4-[4-Cyano-2-(methylsulfanyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide

The reaction was carried out under argon.(4S)-4-[4-Cyano-2-(methylsulfanyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (240 mg, 0.536 mmol; Example 11A) was dissolved in THF (5 ml), andPyBOP (419 mg, 0.805 mmol) and triethylamine (380 mg, 3.76 mmol) wereadded. After brief stirring, the mixture was cooled to 0° C. andammonium chloride (143 mg, 2.68 mmol) was added. The reaction mixturewas stirred at RT overnight, and the contents of the flask was thenadded to 1 N hydrochloric acid. The mixture was extracted twice withethyl acetate, and the combined organic phases were washed with 1 Nhydrochloric acid and with saturated sodium chloride solution, dried andconcentrated. The residue was purified by preparative HPLC. This gave161 mg (67% of theory) of the title compound.

LC-MS (Method 4): R_(t)=0.99 min; MS (ESIpos): m/z (%)=447.1 (100)[M+H]⁺; MS (ESIneg): m/z (%)=445.3 (100) [M−H]⁻.

Example 41(4S)-4-[4-Cyano-2-(methylsulfanyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile

The reaction was carried out under argon.(4S)-4-[4-Cyano-2-(methylsulfanyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide(95.0 mg, 0.213 mmol; Example 40) was dissolved in THF (4 ml), andmethoxycarbonylsulfamoyltriethylammonium hydroxide (Burgess reagent; 101mg, 0.426 mmol) was added. After 30 min of stirring at room temperature,HPLC control showed complete conversion. The mixture was diluted withethyl acetate (4 ml), and water (1 ml) was added. The mixture was thenpassed over a Merck Extrelut® NT3 column, and the filtrate was purifiedby preparative HPLC. Concentration of the product fractions gave 96.0 mg(quantitative) of the title compound.

HPLC (Method 3): R=4.61 min.

MS (DCI/NH₃): m/z=429.1 [M+H]⁺, 446.1 [M+NH₄]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=1.80 (s, 3H), 2.61 (s, 3H), 5.76 (s, 1H),7.67-7.89 (m, 7H), 8.28 (s, 1H).

Example 42(4S)-4-[4-Cyano-2-(methylsulfinyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile

Method A:

(4S)-4-[4-Cyano-2-(methylsulfanyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile(Example 41; 55 mg, 0.13 mmol) was dissolved in ethanol (5.5 ml), andmethyltrioxorhenium (3.20 mg, 0.013 mmol) and hydrogen peroxide (16.0mg, 0.14 mmol) were added. The reaction mixture was stirred at RT for 60min and then concentrated under reduced pressure, and the residue waspurified by preparative HPLC. This gave 27 mg (47% of theory) of thetarget compound as a mixture of diastereomers.

Method B:

(4S)-4-[4-Cyano-2-(methylsulfanyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile(3.00 g, 7.00 mmol; Example 41) was initially charged in methanol/water(5:1, ˜60 ml), sodium periodate (2.85 g, 13.30 mmol; 1.9 eq.) was addedand the mixture was stirred at 30° C. for 16 h. The reaction mixture wasthen poured into saturated aqueous sodium bicarbonate solution (300 ml)and extracted with ethyl acetate (4×75 ml). The combined organic phaseswere dried over sodium sulfate, filtered and concentrated under reducedpressure. The crude product was subjected to flash chromatography onsilica gel (gradient cyclohexane→ethyl acetate). This gave a colorlesssolid (1.6 g, 51% of theory).

LC-MS (Method 4): R_(t)=1.05 min; MS (ESIpos): m/z (%)=445.0 (100)[M+H]⁺.

Example 43(4S)-4-{4-Cyano-2-[(S)-methylsulfinyl]phenyl}-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrileand(4S)-4-{4-cyano-2-[(R)-methylsulfinyl]phenyl}-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile(separation of diastereomers)

(4S)-4-[4-Cyano-2-(methylsulfinyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile(Example 42; 27 mg) was separated into the enantiomerically purediastereomers by preparative HPLC chromatography on a chiral phase[column: Daicel Chiralpak IC, 5 μm, 250 mm×20 mm; sample preparation:the sample was dissolved in 2 ml of methanol+4 ml of MTBE; injectionvolume: 600 μl; mobile phase: MTBE/methanol 80:20; flow rate: 15 ml/min;temperature: 30° C.; detection: 220 nm]. The enantiomeric excess (eevalue) was determined chromatographically [column: Daicel Chiralpak IC,5 μm, 250 mm×4.6 mm; mobile phase: MTBE/methanol 75:25; flow rate: 1ml/min;

temperature: 25° C.; detection: 230 nm].

Diastereomer 1:

Yield: 20 mg

R_(t)=4.71 min, ee>99.0%

LC-MS (Method 6): R_(t)=2.02 min; MS (ESIpos): m/z (%)=445.0 (100)[M+H]⁺; MS (ESIneg): m/z (%)=442.9 (80) [M−H]⁻

¹H-NMR (400 MHz, CDCl₃): δ=1.94 (s, 3H), 2.84 (s, 3H), 5.72 (s, 1H),7.17 (s, 1H), 7.42-7.56 (m, 2H), 7.65 (t, 1H), 7.70-7.79 (m, 2H), 7.90(d, 1H), 8.01 (s, 1H).

Diastereomer 2:

Yield: 7 mg

R_(t)=6.04 min, ee>99.0%

LC-MS (Method 6): R_(t)=2.02 min; MS (ESIpos): m/z (%)=445.0 (100)[M+H]⁺; MS (ESIneg): m/z (%)=442.9 (100) [M−H]⁻

¹H-NMR (400 MHz, CDCl₃): δ=1.97 (s, 3H), 2.77 (s, 3H), 5.97 (br. s, 1H),7.06 (br. s, 1H), 7.31-7.50 (m, 2H), 7.63 (t, 1H), 7.68-7.78 (m, 2H),7.89 (d, 1H), 8.11 (s, 1H).

Example 44(rac)-4-{2,5-Dioxo-1-[3-(trifluoromethyl)phenyl]-2,3,4,5,6,7-hexahydro-1H-pyrrolo[3,4-d]pyrimidin-4-yl}-3-(methylsulfonyl)benzonitrile

(rac)-Ethyl6-(bromomethyl)-4-[4-cyano-2-(methylsulfonyl)phenyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate(200 mg, 0.34 mmol; Example 13A) was dissolved in acetonitrile (4 ml), a7 N solution of ammonia in methanol (5 ml) was added and the mixture wasstirred at RT for 60 min. The reaction mixture was then concentratedunder reduced pressure, and the residue was triturated with acetonitrile(3 ml). The crystals formed were filtered off with suction, washed withacetonitrile and water and, for further purification, separated bypreparative HPLC [column: Sunfire C-18, 5 μm, 19 mm×150 mm; samplepreparation: the sample was dissolved in 3 ml of acetonitrile+3 ml of 1%strength aqueous TFA solution +2 ml of THF; injection volume: 1000 μl;mobile phase: acetonitrile/water/1% aq. TFA 25:60:15 (0-12 min); flowrate: 25 ml/min; temperature: 40° C.; detection: 210 nm]. This gave 59mg (36% of theory) of the target compound.

HPLC (Method 2): R_(t)=3.89 min.

MS (ESIpos): m/z (%)=476.9 (100) [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=3.53 (s, 3H), 3.75 (dd, 2H), 6.61 (s, 1H),7.70-7.86 (m, 4H), 8.01 (s, 1H), 8.08 (s, 1H), 8.16 (d, 1H), 8.27 (d,1H), 8.34 (s, 1H).

Example 45(rac)-4-{6-(2-Hydroxyethyl)-2,5-dioxo-1-[3-(trifluoromethyl)phenyl]-2,3,4,5,6,7-hexahydro-1H-pyrrolo[3,4-d]pyrimidin-4-yl}-3-(methylsulfonyl)benzonitrile

(rac)-Ethyl6-(bromomethyl)-4-[4-cyano-2-(methylsulfonyl)phenyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate(200 mg, 0.34 mmol; Example 13A) was dissolved in acetonitrile (5 ml),2-aminoethanol (62.5 mg, 1.02 mmol) was added and the mixture wasstirred at RT overnight. The reaction mixture was then purified directlyby preparative HPLC (column: Kromasil C18, 125 mm×20 mm, 5 μm, 100 Å;mobile phase A: water with 0.01% formic acid, mobile phase B:acetonitrile; gradient: 0 min 10% B→2 min 10% B→9 min 90% B→12 min 90%B→12.1 min 10% B→15 min 10% B; flow rate: 0.35 ml/min; UV detection: 254nm). This gave 98 mg (54% of theory) of the title compound.

HPLC (Method 2): R_(t)=3.79 min.

MS (ESIpos): m/z (%)=521.1 (100) [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=3.14-3.42 (m, 4H), 3.54 (s, 3H), 3.93 (d,2H), 4.63 (t, 1H), 6.65 (s, 1H), 7.76 (t, 1H), 7.80-7.87 (m, 2H), 8.02(s, 1H), 8.11 (s, 1H), 8.18 (d, 1H), 8.26 (d, 1H), 8.34 (s, 1H).

Example 46(rac)-4-{6-Cyclopropyl-2,5-dioxo-1-[3-(trifluoromethyl)phenyl]-2,3,4,5,6,7-hexahydro-1H-pyrrolo[3,4-d]pyrimidin-4-yl}-3-(methylsulfonyl)benzonitrile

(rac)-Ethyl6-(bromomethyl)-4-[4-cyano-2-(methylsulfonyl)phenyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate(200 mg, 0.34 mmol; Example 13A) was dissolved in acetonitrile (5 ml),cyclopropylamine (58.4 mg, 1.02 mmol) was added and the mixture wasstirred at RT overnight. The reaction mixture was then purified directlyby preparative HPLC (column: Kromasil C18, 125 mm×20 mm, 5 μm, 100 Å;mobile phase A: water with 0.01% formic acid, mobile phase Bacetonitrile; gradient: 0 min 10% B→2 min 10% B→9 min 90% B→12 min 90%B→12.1 min 10% B→15 min 10% B; flow rate: 0.35 ml/min; UV detection: 254nm). The product-containing fractions were combined and once moresubjected to HPLC separation [column: Sunfire C-18, 5 μm, 19 mm×150 mm;sample preparation: the sample was dissolved in 2 ml of acetonitrile+2ml of 1% strength aqueous TFA solution +1 ml of THF; injection volume:1000 μl; mobile phase: acetonitrile/water/1% aq. TFA 35:52:13 (0-10min); flow rate: 25 ml/min; temperature: 40° C.; detection: 210 nm].This gave 38 mg (22% of theory) of the title compound.

HPLC (Method 2): R_(t)=4.24 min.

MS (ESIpos): m/z (%)=516.9 (100) [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=0.48-0.60 (m, 4H), 2.43-2.48 (m, 1H), 3.54(s, 3H), 3.81 (s, 2H), 6.62 (s, 1H), 7.74 (t, 1H), 7.80-7.85 (m, 2H),7.98 (s, 1H), 8.10-8.17 (m, 2H), 8.26 (d, 1H), 8.34 (s, 1H).

Example 47(rac)-4-{6-Ethyl-2,5-dioxo-1-[3-(trifluoromethyl)phenyl]-2,3,4,5,6,7-hexahydro-1H-pyrrolo[3,4-d]pyrimidin-4-yl}-3-(methylsulfonyl)benzonitrile

(rac)-Ethyl6-(bromomethyl)-4-[4-cyano-2-(methylsulfonyl)phenyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate(200 mg, 0.34 mmol; Example 13A) was dissolved in acetonitrile (5 ml),ethylamine (46.1 mg, 1.02 mmol) was added and the mixture was stirred atRT overnight. The reaction mixture was then purified directly bypreparative HPLC (column: Kromasil C18, 125 mm×20 mm, 5 μm, 100 Å;mobile phase A: water with 0.01% formic acid, mobile phase B:acetonitrile; gradient: 0 min 10% B→2 min 10% B→9 min 90% B→12 min 90%B→12.1 min 10% B→15 min 10% B; flow rate: 0.35 ml/min; UV detection: 254nm). This gave 120 mg (70% of theory) of the title compound.

HPLC (Method 2): R_(t)=4.20 min.

MS (ESIpos): m/z (%)=505.0 (100) [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=0.94 (t, 3H), 3.11-3.26 (m, 2H), 3.54 (s,3H), 3.86 (s, 2H), 6.64 (s, 1H), 7.75 (t, 1H), 7.80-7.88 (m, 2H), 8.02(s, 1H), 8.10 (s, 1H), 8.17 (d, 1H), 8.26 (d, 1H), 8.34 (s, 1H).

Example 484-{(4S)-6-Ethyl-2,5-dioxo-1-[3-(trifluoromethyl)phenyl]-2,3,4,5,6,7-hexahydro-1H-pyrrolo[3,4-d]pyrimidin-4-yl}-3-(methylsulfonyl)benzonitrile

(rac)-4-{6-Ethyl-2,5-dioxo-1-[3-(trifluoromethyl)phenyl]-2,3,4,5,6,7-hexahydro-1H-pyrrolo[3,4-d]pyrimidin-4-yl}-3-(methylsulfonyl)benzonitrile(Example 47; 120 mg) was separated into the enantiomers by preparativeHPLC chromatography on a chiral phase [column: Daicel Chiralpak IC, 5μm, 250 mm×20 mm; sample preparation: the sample was dissolved in 1 mlof methanol+1 ml of acetonitrile+3 ml of MTBE; injection volume: 700 μl;mobile phase: MTBE/methanol 80:20; flow rate: 15 ml/min; temperature:30° C.; detection: 220 nm]. This gave 42 mg (84% of theory, >99.0% ee)of the 4S enantiomer. The enantiomeric excess (ee value) was determinedchromatographically [column: Daicel Chiralpak IC, 5 μm, 250 mm×4.6 mm;mobile phase: MTBE/methanol 80:20; flow rate: 1 ml/min; temperature: 25°C.; detection: 230 nm; R_(t)=6.83 min].

HPLC (Method 2): R_(t)=4.20 min.

MS (DCI/NH₃): m/z (%)=505.1 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=0.94 (t, 3H), 3.10-3.27 (m, 2H), 3.54 (s,3H), 3.86 (s, 2H), 6.64 (s, 1H), 7.75 (t, 1H), 7.80-7.88 (m, 2H), 8.02(s, 1H), 8.10 (s, 1H), 8.17 (d, 1H), 8.26 (d, 1H), 8.34 (s, 1H).

Optical rotation: [α]²⁰ _(Na)=−107° (c=0.230 in acetone).

Example 49(rac)-N-(2-{4-[4-Cyano-2-(methylsulfonyl)phenyl]-2,5-dioxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4,5,7-hexahydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl}ethyl)acetamide

(rac)-Ethyl6-(bromomethyl)-4-[4-cyano-2-(methylsulfonyl)phenyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate(200 mg, 0.34 mmol; Example 13A) was dissolved in acetonitrile (5 ml),N-(2-aminoethyl)acetamide (105 mg, 1.02 mmol) was added and the mixturewas stirred at RT overnight. The reaction mixture was then purifieddirectly by preparative HPLC (column: Kromasil C18, 125 mm×20 mm, 5 μm,100 Å; mobile phase A: water with 0.01% formic acid, mobile phase B:acetonitrile; gradient: 0 min 10% B→2 min 10% B→9 min 90% B→12 min 90%B→12.1 min 10% B→15 min 10% B; flow rate: 0.35 ml/min; UV detection: 254nm). This gave 107 mg (56% of theory) of the title compound.

HPLC (Method 2): R_(t)=3.78 min.

MS (DCI/NH₃): m/z (%)=562.1 (25) [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=1.66 (s, 3H), 2.97-3.24 (m, 4H), 3.54 (s,3H), 3.91 (s, 2H), 6.64 (s, 1H), 7.73-7.86 (m, 4H), 7.98 (s, 1H),8.11-8.17 (m, 2H), 8.27 (d, 1H), 8.34 (s, 1H).

Example 50(rac)-1-(2-{4-[4-Cyano-2-(methylsulfonyl)phenyl]-2,5-dioxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4,5,7-hexahydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl}ethyl)urea

(rac)-Ethyl6-(bromomethyl)-4-[4-cyano-2-(methylsulfonyl)phenyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate(200 mg, 0.34 mmol; Example 13A) was dissolved in acetonitrile (5 ml),1-(2-aminoethyl)urea (106 mg, 1.02 mmol) was added and the mixture wasstirred at RT overnight. The reaction mixture was then purified directlyby preparative HPLC (column: Kromasil C18, 125 mm×20 mm, 5 μm, 100 Å;mobile phase A: water with 0.01% formic acid, mobile phase B:acetonitrile; gradient: 0 min 10% B→2 min 10% B→9 min 90% B →12 min 90%B→12.1 min 10% B→15 min 10% B; flow rate: 0.35 ml/min; UV detection: 254nm). This gave 69 mg (34% of theory) of the title compound.

HPLC (Method 2): R_(t)=3.69 min.

MS (DCI/NH₃): m/z (%)=563.1 (100) [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=2.90-3.24 (m, 4H), 3.54 (s, 3H), 3.94 (m,2H), 5.42 (s, 2H), 5.85 (t, 1H), 6.63 (s, 1H), 7.73-7.86 (m, 3H), 7.98(s, 1H), 8.10-8.14 (m, 2H), 8.27 (d, 1H), 8.34 (s, 1H).

Example 51(4S)-4-[4-Cyano-2-(methylsulfonyl)phenyl]-3-[(3-hydroxyazetidin-1-yl)carbonyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile

According to the General Procedure 1, 4-nitrophenyl(6S)-5-cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidin-1(2H)-carboxylate(80.0 mg, 0.128 mmol; Example 6A) was reacted with azetidin-3-olhydrochloride (42.0 mg, 0.384 mmol) in acetonitrile (1 ml) to give thetarget compound (40 mg, 56% of theory).

HPLC (Method 2): R_(t)=4.20 min.

MS (DCI/NH₃): m/z (%)=560 [M+H]⁺, 577.2 [M+NH₄]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=1.81 (s, 3H), 3.38-3.61 (m, 4H), 3.79-4.08(m, 2H), 4.22-4.45 (m, 2H), 5.74 (t, 1H), 6.83 (s, 1H), 7.74-7.90 (m,3H), 8.00 (s, 1H), 8.12 (br. s, 1H), 8.36-8.43 (m, 2H).

Example 52(4S)-4-[4-Cyano-2-(methylsulfonyl)phenyl]-3-[(3-hydroxypyrrolidin-1-yl)carbonyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidin-5-carbonitrile

According to the General Procedure 1, 4-nitrophenyl(6S)-5-cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidine-1(2H)-carboxylate(78.0 mg, 0.125 mmol; Example 6A) was reacted with pyrrolidin-3-ol (32.6mg, 0.374 mmol) in acetonitrile (1 ml) to give the target compound (58mg, 81% of theory).

HPLC (Method 2): R_(t)=4.31 min.

MS (ESIpos): m/z (%)=574.3 (100) [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=1.61-1.93 (m, 5H), 2.87-3.26 (m, 2H),3.42-3.84 (m, 5H), 4.13-4.29 (m, 1H), 4.83-5.10 (m, 1H), 6.84 (s, 1H),7.73-7.90 (m, 3H), 7.98-8.42 (m, 4H).

Example 53(4S)-4-[4-Cyano-2-(methylsulfonyl)phenyl]-3-[(3R)-3-methoxypiperidin-1-yl]carbonyl-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile

According to the General Procedure 1, 4-nitrophenyl(6S)-5-cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidine-1(2H)-carboxylate(80.0 mg, 0.128 mmol; Example 6A) was reacted with(3R)-3-methoxypiperidine (44.2 mg, 0.384 mmol) in acetonitrile (1 ml) togive the target compound (45 mg, 57% of theory).

HPLC (Method 2): R_(t)=4.70 min.

MS (ESIpos): m/z (%)=602.0 (100) [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=1.15-1.94 (m, 7H), 2.63-4.24 (m, 11H),6.76-6.88 (m, 1H), 7.38-8.55 (m, 7H).

Example 54(4S)-4-[4-Cyano-2-(methylsulfonyl)phenyl]-3-[(3-hydroxypiperidin-1-yl)carbonyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile

According to the General Procedure 1, 4-nitrophenyl(6S)-5-cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidine-1(2H)-carboxylate(80.0 mg, 0.128 mmol; Example 6A) was reacted with piperidin-3-ol (38.8mg, 0.384 mmol) in acetonitrile (1 ml) to give the target compound (58mg, 77% of theory).

HPLC (Method 2): R_(t)=4.31 min.

MS (DCI/NH₃): m/z (%)=588 [M+H]⁺, 605.2 [M+NH₄]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=0.78-1.92 (m, 7H), 2.24-5.00 (m, 9H),6.75-6.87 (m, 1H), 7.72-8.07 (m, 4H), 8.18-8.52 (m, 3H).

Example 55(4S)-3-[(3R)-3-Aminopiperidin-1-yl]carbonyl-4-[4-cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile

tert-Butyl[(3R)-1-{[(6S)-5-cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl}-3,6-dihydropyrimidin-1(2H)-yl]carbonyl]piperidin-3-yl]carbamate(Example 12A; 56.0 mg, 0.082 mmol) was dissolved in a 4 N solution ofhydrogen chloride in dioxane (2.15 ml) and stirred at RT for 60 min. Thecontents of the flask was then concentrated under reduced pressure, andthe residue was taken up in dichloromethane (15 ml) and 2 N aqueoussodium hydroxide solution (15 ml). After extraction, the organic phasewas separated off, dried over sodium sulfate and concentrated underreduced pressure. This gave 47 mg (96% of theory) of the title compound.

HPLC (Method 2): R_(t)=4.17 min.

MS (ESIpos): m/z (%)=587.0 (100) [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=1.40-1.84 (m, 7H), 2.03-2.35 (m, 2H),2.74-2.90 (m, 1H), 3.52 (s, 3H), 3.74-4.05 (m, 1H), 6.67 (br. s, 1H),6.80 (s, 1H), 7.27 (br. s, 1H), 7.73-8.06 (m, 4H), 8.21 (d, 1H), 8.37(s, 1H), 8.48 (d, 1H).

General Procedure 2: Synthesis of N-aminocarbonyldihydropyrimidinoneDerivatives (Process B)

0.1 mmol of the appropriate amine was dissolved in 0.2 ml ofacetonitrile, and 25.8 mg (0.2 mmol) of diisopropylethylamine and 62.5mg (0.1 mmol) of 4-nitrophenyl(6S)-5-cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidine-1(2H)-carboxylate(Example 6A), dissolved in 0.6 ml of acetonitrile, were added. Thereaction mixture was stirred at room temperature overnight, and theacetonitrile was then evaporated in a vacuum centrifuge. The crudeproduct was dissolved in 0.5 ml of DMSO and purified by preparativeHPLC/MS (Method 7).

The exemplary embodiments shown in table 1 below were prepared accordingto the General Procedure 2:

TABLE 1 Example LC/MS data No. Structure (Method 7) 56

MS (ESIpos): m/z = 616 (M + H)⁺; R_(t) = 2.01 min 57

MS (ESIpos): m/z = 590 (M + H)⁺; R_(t) = 2.21 min 58

MS (ESIpos): m/z = 601 (M + H)⁺; R_(t) = 1.97 min 59

MS (ESIpos): m/z = 655 (M + H)⁺; R_(t) = 1.57 min 60

MS (ESIpos): m/z = 641 (M + H)⁺; R_(t) = 1.61 min 61

MS (ESIpos): m/z = 588 (M + H)⁺; R_(t) = 2.04 min 62

MS (ESIpos): m/z = 602 (M + H)⁺; R_(t) = 2.09 min 63

MS (ESIpos): m/z = 602 (M + H)⁺; R_(t) = 2.03 min 64

MS (ESIpos): m/z = 588 (M + H)⁺; R_(t) = 1.96 min 65

MS (ESIpos): m/z = 619 (M + H)⁺; R_(t) = 1.51 min 66

MS (ESIpos): m/z = 641 (M + H)⁺; R_(t) = 1.54 min 67

MS (ESIpos): m/z = 630 (M + H)⁺; R_(t) = 2.07 min 68

MS (ESIpos): m/z = 631 (M + H)⁺; R_(t) = 1.55 min 69

MS (ESIpos): m/z = 650 (M + H)⁺; R_(t) = 1.74 min 70

MS (ESIpos): m/z = 651 (M + H)⁺; R_(t) = 2.18 min 71

MS (ESIpos): m/z = 620 (M + H)⁺; R_(t) = 1.97 min 72

MS (ESIpos): m/z = 590 (M + H)⁺; R_(t) = 1.84 min 73

MS (ESIpos): m/z = 602 (M + H)⁺; R_(t) = 2.02 min 74

MS (ESIpos): m/z = 635 (M + H)⁺; R_(t) = 1.80 min 75

MS (ESIpos): m/z = 601 (M + H)⁺; R_(t) = 1.53 min 76

MS (ESIpos): m/z = 587 (M + H)⁺; R_(t) = 1.89 min 77

MS (ESIpos): m/z = 617 (M + H)⁺; R_(t) = 1.56 min 78

MS (ESIpos): m/z = 615 (M + H)⁺; R_(t) = 1.54 min 79

MS (ESIpos): m/z = 602 (M + H)⁺; R_(t) = 2.17 min 80

MS (ESIpos): m/z = 620 (M + H)⁺; R_(t) = 2.00 min 81

MS (ESIpos): m/z = 616 (M + H)⁺; R_(t) = 2.03 min 82

MS (ESIpos): m/z = 644 (M + H)⁺; R_(t) = 2.25 min 83

MS (ESIpos): m/z = 588 (M + H)⁺; R_(t) = 2.03 min 84

MS (ESIpos): m/z = 602 (M + H)⁺; R_(t) = 2.19 min 85

MS (ESIpos): m/z = 576 (M + H)⁺; R_(t) = 2.12 min 86

MS (ESIpos): m/z = 618 (M + H)⁺; R_(t) = 2.31 min 87

MS (ESIpos): m/z = 606 (M + H)⁺; R_(t) = 2.13 min 88

MS (ESIpos): m/z = 588 (M + H)⁺; R_(t) = 2.14 min 89

MS (ESIpos): m/z = 658 (M + H)⁺; R_(t) = 2.21 min

General Procedure 3: Synthesis of N-sulfonyldihydropyrimidinoneDerivatives

Under argon, 35.4 mg (0.077 mmol) of(4S)-4-[4-cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile(Example 6) were dissolved in 0.4 ml of THF, 4.6 mg (0.192 mmol) ofsodium hydride were added at 0° C. and the mixture was stirred at roomtemperature for 20 min. A solution of 0.0924 mmol of the appropriatesulfonyl chloride in 0.2 ml of THF was then added, and the mixture wasstirred at room temperature for a further 30 min. 50 mg (0.93 mmol) ofammonium chloride were then added, and the THF was evaporated in avacuum centrifuge. The crude product was taken up in 0.5 ml of DMSO andfiltered, and the filtrate was purified by preparative HPLC/MS (Method7). The exemplary embodiments shown in table 2 below were preparedaccording to the General Procedure 3:

TABLE 2 Example LC/MS data No. Structure (Method 7)  90

MS (ESIpos): m/z = 632 (M + H)⁺; R_(t) = 2.17 min  91

MS (ESIpos): m/z = 619 (M + H)⁺; R_(t) = 2.26 min  92

MS (ESIpos): m/z = 619 (M + H)⁺; R_(t) = 1.88 min  93

MS (ESIpos): m/z = 621 (M + H)⁺; R_(t) = 2.24 min  94

MS (ESIpos): m/z = 645 (M + H)⁺; R_(t) = 2.28 min  95

MS (ESIpos): m/z = 657 (M + H)⁺; R_(t) = 2.37 min  96

MS (ESIpos): m/z = 655 (M + H)⁺; R_(t) = 2.21 min  97

MS (ESIpos): m/z = 654 (M + H)⁺; R_(t) = 2.30 min  98

MS (ESIpos): m/z = 642 (M + H)⁺; R_(t) = 2.29 min  99

MS (ESIpos): m/z = 641 (M + H)⁺; R_(t) = 2.18 min 100

MS (ESIpos): m/z = 637 (M + H)⁺; R_(t) = 2.23 min 101

MS (ESIpos): m/z = 633 (M + H)⁺; R_(t) = 2.16 min 102

MS (ESIpos): m/z = 631 (M + H)⁺; R_(t) = 2.23 min 103

MS (ESIpos): m/z = 626 (M + H)⁺; R_(t) = 2.17 min 104

MS (ESIpos): m/z = 621 (M + H)⁺; R_(t) = 2.33 min 105

MS (ESIpos): m/z = 620 (M + H)⁺; R_(t) = 2.23 min 106

MS (ESIpos): m/z = 619 (M + H)⁺; R_(t) = 2.16 min 107

MS (ESIpos): m/z = 619 (M + H)⁺; R_(t) = 2.27 min 108

MS (ESIpos): m/z = 619 (M + H)⁺; R_(t) = 2.21 min 109

MS (ESIpos): m/z = 615 (M + H)⁺; R_(t) = 2.27 min 110

MS (ESIpos): m/z = 615 (M + H)⁺; R_(t) = 2.26 min 111

MS (ESIpos): m/z = 607 (M + H)⁺; R_(t) = 2.28 min 112

MS (ESIpos): m/z = 594 (M + H)⁺; R_(t) = 2.28 min 113

MS (ESIpos): m/z = 657 (M + H)⁺; R_(t) = 2.38 min 114

MS (ESIpos): m/z = 661 (M + H)⁺; R_(t) = 2.22 min

Example 115 (rac)-Ethyl4-[4-cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The reaction was carried out under argon. Triethyl phosphate (4.18 g,22.9 mmol) and diphosphorus pentoxide (2.17 g, 15.3 mmol) were stirredat 50° C. overnight. The mixture was then diluted with methyl tert-butylether (60 ml), and 4-formyl-3-(methylsulfonyl)benzonitrile (4.00 g, 19.1mmol; Example 4A), 1-[3-(trifluoromethyl)phenyl]urea (3.90 g, 19.1 mmol)and ethyl acetoacetate (3.73 g, 28.7 mmol) were then added. The mixturewas stirred under reflux overnight. The precipitate formed was filteredoff with suction and washed with diethyl ether (300 ml). Since thereaction had not entirely gone to completion, once more triethylphosphate (5.36 g, 29.4 mmol) and diphosphorus pentoxide (2.71 g, 19.1mmol) were stirred at 50° C. overnight and then stirred with the solidisolated beforehand and methyl tert-butyl ether (25 ml) under reflux fora further night. The precipitate formed was again filtered off withsuction and washed with diethyl ether. This gave 5.93 g (61% of theory)of the target compound.

HPLC (Method 2): R_(t)=4.56 min.

MS (DCI/NH₃): m/z=508.1 [M+H]⁺, 525 [M+NH₄]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=0.94 (t, 3H), 2.13 (s, 3H), 3.50 (s, 3H),3.89-4.02 (q, 2H), 6.41 (s, 1H), 7.25 (s, 1H), 7.68-7.90 (m, 4H), 8.09(d, 1H), 8.26 (d, 1H), 8.39 (s, 1H).

Example 116(4S)-3-(Cyanomethyl)-4-[4-cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile

The reaction was carried out under argon.(4S)-4-[4-Cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile(115 mg, 250 μmol) was initially charged in THF (1 ml) at 0° C., sodiumhydride (14 mg, 350 μmol; 1.4 eq.) was added and the mixture was stirredfor 20 min. After addition of bromoacetonitrile (50 mg, 376 μmol; 1.5eq.), the mixture was stirred at RT for 120 min. The reaction mixturewas then purified directly by preparative HPLC (column: Gromsil, C-18 5μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→75:25). This gavethe title compound as a colorless solid (85 mg, 68% of theory).

LC-MS (Method 6): R_(t)=2.39 min; MS (ESIpos): m/z (%)=500.1 (100)[M+H]⁺; MS (ESIneg): m/z (%)=498.0 (100) [M−H]⁻

¹H-NMR (400 MHz, DMSO-d₆): δ=1.84 (s, 3H), 3.56 (s, 3H), 4.20 (d, 1H),4.30 (d, 1H), 6.60 (s, 1H), 7.70-8.50 (m, 7H).

Example 117(4S)-4-[4-Cyano-2-(methylsulfonyl)phenyl]-3-(4-cyanophenyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile

The reaction was carried out under argon.(4S)-4-[4-Cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile(100 mg, 217 μmol), 4-cyanophenylboronic acid (127.7 mg, 869 μmol; 4eq.), copper(II) acetate (158 mg, 869 μmol; 4 eq.) and 4 Å molecularsieve (500 mg) were initially charged in dichloromethane (5 ml),pyridine (281 μl; 16 eq.) and triethylamine (121 μl; 4 eq.) were addedand the mixture was subsequently stirred at RT for 4 days. The reactionmixture was then filtered through kieselguhr which was then repeatedlywashed with methanol, and the filtrate was concentrated under reducedpressure. The crude product was purified by preparative HPLC (column:Gromsil, C-18 5 μm; mobile phase: acetonitrile/water+0.1% TFA10:90→80:20). This gave the title compound as a colorless solid (25 mg,19.5% of theory).

LC-MS (Method 10): R_(t)=2.34 min; MS (ESIpos): m/z (%)=562.0 (100)[M+H]⁺; MS (ESIneg): m/z (%)=416.1 (100), 560.2 (50) [M−H]⁻

¹H-NMR (400 MHz, DMSO-d₆): δ=1.90 (s, 3H), 3.00 (s, 3H), 7.10 (s, 1H),7.40 (m, 2H), 7.70-8.70 (m, 9H).

Example 118(4S)-4-[4-Cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1,3-bis[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile

The reaction was carried out under argon.(4S)-4-[4-Cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile(100 mg, 217 μmol), 3-(trifluoromethyl)phenylboronic acid (165 mg, 869μmol; 4 eq.), copper(II) acetate (158 mg, 869 μmol; 4 eq.) and 4 Åmolecular sieve (500 mg) were initially charged in dichloromethane (5ml), pyridine (281 μl; 16 eq.) and triethylamine (121 μl; 4 eq.) wereadded and the mixture was subsequently stirred at RT for 20 h. Thereaction mixture was then filtered through kieselguhr which was thenwashed repeatedly with methanol, and the filtrate was concentrated underreduced pressure. The crude product was purified by preparative HPLC(Column: Gromsil, C-18 5 μm; mobile phase: acetonitrile/water+0.1% TFA10:90→90:10). This gave the title compound as a colorless solid (34 mg,26% of theory).

LC-MS (Method 4): R_(t)=1.39 min; MS (ESIpos): m/z (%)=605.0 (100)[M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=1.90 (s, 3H), 3.00 (s, 3H), 7.10 (s, 1H),7.30 (m, 1H), 7.50 (m, 1H), 7.60 (m, 1H), 7.70 (m, 1H), 7.70-8.70 (m,7H).

Example 119(4S)-4-[4-Cyano-2-(methylsulfonyl)phenyl]-6-methyl-3-[(4-methylphenyl)sulfonyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile

The reaction was carried out under argon.(4S)-4-[4-Cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile(278 mg, 604 μmol) was initially charged in dry THF (6 ml), and sodiumhydride (60% in mineral oil; 34 mg, 845 μmol; 1.4 eq.) was added at 0°C. The mixture was warmed to RT and stirred for 20 min. A solution ofp-toluenesulfonyl chloride (161 mg, 845 μmol; 1.4 eq.) in THF (˜2 ml)was then slowly added dropwise. After a reaction time of 16 h, thereaction mixture was concentrated and the crude product was purified bypreparative HPLC (column: Gromsil C-18 10 μm; mobile phase:acetonitrile/water+0.1% TFA 10:90→90:10). This gave the title compoundas a colorless solid (358 mg, 96% of theory).

LC-MS (Method 4): R_(t)=1.38 min; MS (ESIpos): m/z (%)=615.2 (100)[M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=1.75 (s, 3H), 2.40 (s, 3H), 3.50 (s, 3H),7.30-7.40 (m, 4H), 7.60 (s, 1H), 7.70 (m, 2H), 7.85-7.90 (m, 2H), 8.13(m, 1H), 8.25 (m, 1H), 8.65 (s, 1H).

Example 120 Benzyl5-cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidine-1(2H)-carboxylate

The reaction was carried out under argon.(4S)-4-[4-Cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile(115 mg, 250 μmol) was initially charged in dry THF (3 ml), and sodiumhydride (60% in mineral oil; 14 mg, 350 μmol; 1.4 eq.) was added at 0°C. The mixture was warmed to RT and stirred for 20 min. A solution ofbenzyl chloroformate (60 mg, 350 μmol; 1.4 eq.) in THF (1 ml) was thenslowly added dropwise. After a reaction time of 1.5 h, the reactionmixture was concentrated and the crude product was purified bypreparative HPLC (column: Gromsil C-18 10 μm; mobile phase:acetonitrile/water+0.1% TFA 10:90→90:10). This gave the title compoundas a colorless solid (68 mg, 46% of theory).

LC-MS (Method 9): R_(t)=1.22 min; MS (ESIpos): m/z (%)=595 (10) [M+H]⁺;MS (ESIneg): m/z (%)=416.2 (100), 593.4 (50) [M−H]⁻

¹H-NMR (400 MHz, DMSO-d₆): δ=1.80 (s, 3H), 3.45 (s, 3H), 5.20 (s, 2H),7.15 (m, 1H), 7.25-7.30 (m, 5H), 7.75-7.90 (m, 3H), 8.05 (br. s, 2H),8.30 (dd, 1H), 8.50 (d, 1H).

Example 121(4S)-4-[4-Cyano-2-(methylsulfonyl)phenyl]-3-[2-(diethylamino)ethyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitriletrifluoroacetate

The reaction was carried out under argon.(4S)-4-[4-Cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile(100 mg, 217 μmol) was initially charged in dry THF (5 ml), sodiumhydride (60% in mineral oil; 22 mg, 543 μmol; 2.5 eq.) was added at 0°C. and the mixture was stirred for 20 min. 2-Bromo-N,N-diethylethanaminehydrobromide (85 mg, 326 μmol; 1.5 eq.) was then added, and the mixturewas stirred at RT for 90 minutes. The reaction was then added tosaturated sodium chloride solution (50 ml) and extracted with ethylacetate (3×30 ml). The combined organic phases were dried over solidsodium sulfate, filtered and concentrated under reduced pressure. Thecrude product was purified by preparative HPLC (column: Gromsil C-18 10μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→75:25). The titlecompound was obtained as a colorless solid (112 mg, 77% of theory).

LC-MS (Method 5): R_(t)=1.34 min; MS (ESIpos): m/z (%)=560.2 (100)[M+H]⁺; MS (ESIneg): m/z (%)=558.3 (100) [M−H]⁻

¹H-NMR (400 MHz, DMSO-d₆): δ=1.12 (t, 6H), 1.85 (s, 3H), 3.10 (br. m,6H), 3.30 (m, 1H), 3.55 (s, 3H), 3.70 (m, 1H), 6.55 (s, 1H), 7.70-8.40(m, 6H), 8.51 (s, 1H), 9.10 (br. s, 1H).

Example 122 Allyl(4S)-4-[4-cyano-2-(methylsulfonyl)phenyl]-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The reaction was carried out under argon. Allyl(4S)-4-[4-cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate(260 mg, 0.5 mmol) was initially charged in THF (10 ml) at −78° C., anda 1 M solution of lithium hexamethyldisilazide (LiHMDS) in THF (0.6 ml;1.2 eq.) was added. After 20 min of stirring, iodomethane (355 mg; 5eq.) was added, and the mixture was stirred with gradual warming from−78° C. to RT for 16 h. The reaction mixture was then concentrated, andthe residue was subjected to flash chromatography on silica gel (mobilephase: cyclohexane→cyclohexane/ethyl acetate 55:45). This gave the titlecompound as a solid (157 mg, 59% of theory).

LC-MS (Method 5): R_(t)=2.30 min; MS (ESIpos): m/z (%)=534.1 (100)[M+H]⁺; MS (ESIneg): m/z (%)=532.1 (100) [M−H]⁻.

Example 1234-(4S)-3,6-Dimethyl-2,5-dioxo-1-[3-(trifluoromethyl)phenyl]-2,3,4,5,6,7-hexahydro-1H-pyrrolo[3,4-d]pyrimidin-4-yl-3-(methylsulfonyl)benzonitrile

Under an argon protective gas atmosphere, a 1 M solution of methylaminein THF (20.7 ml, 20.7 mmol, 20 eq.) was added to 2,3-dibromopropyl(4S)-6-(bromomethyl)-4-[4-cyano-2-(methylsulfonyl)phenyl]-3-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate(801 mg, 1.04 mmol), and the mixture was stirred initially at RT for 2 hand then at 5° C. for a further 16 h. The reaction mixture was thenconcentrated under reduced pressure, and the crude product was purifiedby preparative HPLC (column: Gromsil C-18 10 μm; mobile phase:acetonitrile/water+0.1% TFA 10:90→75:25). This gave the title compoundas a solid (314 mg, 60% of theory).

LC-MS (Method 5): R_(t)=1.82 min; MS (ESIpos): m/z (%)=505.1 (100)[M+H]⁺; MS (ESIneg): m/z (%)=503.1 (100) [M−H]⁻

¹H-NMR (400 MHz, DMSO-d₆): δ=2.70 (2s, 6H), 3.70 (s, 3H), 3.90 (m, 2H),6.60 (s, 1H), 7.80 (m, 1H), 7.90 (m, 2H), 8.00 (br. s, 1H), 8.20 (m,1H), 8.25 (m, 1H), 8.40 (m, 1H).

Example 124 Allyl(rac)-4-[4-cyano-2-(ethylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The reaction was carried out under argon. Triethyl phosphate (0.718 g,3.9 mmol) and diphosphorus pentoxide (0.511 g) were stirred at 40° C.overnight. The mixture was then diluted with MTBE (30 ml), and4-formyl-3-(ethylsulfonyl)benzonitrile (0.88 g, 3.94 mmol),1-[3-(trifluoromethyl)phenyl]urea (0.805 g, 3.94 mmol) and allylacetoacetate (0.841 g, 5.91 mmol; 1.5 eq.) were added. The mixture wasthen stirred under reflux for 4 h. The reaction mixture was thenconcentrated by distillative removal of MTBE and subsequently heated at90° C. for a further 2 h. For work-up, residual solvent was removedunder reduced pressure, and the residue was suspended in MTBE (20 ml)and then filtered off with suction. The solid was washed with MTBE (10ml). This gave 1.34 g (42% of theory) of the title compound.

LC-MS (Method 4): R_(t)=1.33 min; MS (ESIpos): m/z (%)=534.1 (100)[M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=1.20 (t, 3H), 2.15 (s, 3H), 3.54 (m, 2H),4.45 (m, 2H), 4.95 (d, 1H), 5.05 (d, 1H), 5.70 (m, 1H), 6.25 (d, 1H),7.00 (d, 1H), 7.70-7.85 (m, 4H), 8.10 (br. d, 1H), 8.30 (m, 1H), 8.35(s, 1H).

Example 125(rac)-4-[4-Cyano-2-(ethylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide

The reaction was carried out under argon.(rac)-4-[4-Cyano-2-(ethylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (1100 mg, 2.29 mmol) and HATU (2 eq., 1695 mg, 4.5 mmol) wereinitially charged in dry DMF (28 ml) at 0° C., and a 0.5 M solution ofammonia in dioxane (6 eq., 23.6 ml, 13.4 mmol) and DIEA (2 eq., 576 mg,4.5 mmol) were added after brief stirring (20 min). The mixture wasstirred at RT for 3 h (HPLC control). The reaction mixture was thendiluted with ethyl acetate (200 ml). The organic phase was washedsuccessively with saturated sodium bicarbonate solution (50 ml), 10%strength citric acid (3×50 ml) and saturated sodium chloride solution(50 ml), dried over solid sodium sulfate, filtered and concentrated. Theresidue was subjected to flash chromatography on silica gel (mobilephase: dichloromethane→dichloromethane/methanol 50:3). This gave acolorless solid (1050 mg, 96% of theory).

LC-MS (Method 5): R_(t)=1.57 min; MS (ESIpos): m/z (%)=493.0 (100)[M+H]⁺; MS (ESIneg): m/z (%)=448.1 (100), 491.1 (90) [M−H]⁻

¹H-NMR (400 MHz, DMSO-d₆): δ=1.16 (t, 3H), 1.80 (s, 3H), 3.57 (m, 2H),6.25 (s, 1H), 7.20 (m, 1H), 7.30 (br. s, 1H), 7.45 (br. s, 1H),7.65-7.80 (m, 4H), 8.10 (d, 1H), 8.25 (s, 1H), 8.35 (dd, 1H).

Example 126(rac)-4-[4-Cyano-2-(ethylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile

The reaction was carried out under argon.(rac)-4-[4-Cyano-2-(ethylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide(1000 mg, 2.03 mmol) was initially charged in dry THF (50 ml),methoxycarbonylsulfamoyltriethylammonium hydroxide (Burgess reagent; 726mg, 3.046 mmol) was added and the mixture was stirred at RT. After 75min, HPLC control showed complete conversion. Water (20 ml) was thenadded, the reaction mixture was concentrated and the residue was takenup in ethyl acetate (200 ml). The organic phase was washed withsaturated sodium chloride solution (3×50 ml), dried over solid sodiumsulfate, filtered and concentrated. The residue was subjected to flashchromatography on silica gel (mobile phase:cyclohexane→cyclohexane/ethyl acetate 2:3). The title compound wasobtained as a colorless solid (890 mg, 92% of theory).

LC-MS (Method 6): R_(t)=2.34 min; MS (ESIpos): m/z (%)=475.0 (100)[M+H]⁺; MS (ESIneg): m/z (%)=473.1 (100) [M−H]⁻

¹H-NMR (400 MHz, DMSO-d₆): δ=1.20 (t, 3H), 1.80 (s, 3H), 3.45 (m, 2H),6.35 (s, 1H), 7.70-7.85 (m, 3H), 7.95 (br. s, 1H), 8.30-8.40 (m, 4H).

Example 127(4S)-4-[4-Cyano-2-(ethylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile

(rac)-4-[4-Cyano-2-(ethylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile(0.83 g) was separated into the enantiomers by preparative HPLCchromatography on a chiral phase [column: chiral silica gel phase basedon the selector poly(N-methacryloyl-D-leucinedicyclopropylmethylamide);column dimensions: 670 mm×40 mm; sample preparation: solution in ethylacetate (30 ml); injection volume: 6.1 ml; mobile phase: isohexane/ethylacetate 3:7; flow rate 50 ml/min; temperature: 24° C.; detection: 260nm]. This gave 0.379 g (89% of theory; >99.9% ee) of the 4S enantiomers.The enantiomeric excess (ee value) was determined chromatographically[column: chiral silica gel phase based on the selectorpoly(N-methacryloyl-D-leucinedicyclopropylmethylamide); columndimensions: 250 mm×4.6 mm; mobile phase: isohexane/ethyl acetate 1:1;flow rate: 2 ml/min; detection: 260 nm; R_(t)=4.26 min (4R enantiomer:R_(t)=8.87 min)].

LC-MS (Method 4): R_(t)=1.18 min; MS (ESIpos): m/z (%)=475.1 (100)[M+H]⁺.

For the ¹H-NMR data, see the racemic compound (Example 126).

Example 128(4S)-4-[4-Cyano-2-(ethylsulfonyl)phenyl]-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile

The reaction was carried out under argon.(4S)-4-[4-Cyano-2-(ethylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile(71.2 mg, 0.15 mmol) was initially charged in absolute THF (6 ml), and a1 M solution of lithium hexamethyldisilazide (LiHMDS) in THF (180 μl;1.2 eq.) was added at −78° C. After 20 min of stirring, iodomethane (47μl; 5 eq.) was added, and the mixture was stirred with gradual warmingfrom −78° C. to RT for 60 h. The reaction mixture was then purifieddirectly by preparative HPLC (column: Gromsil, C-18 10 μm; mobile phase:acetonitrile/water+0.1% TFA 10:90→80:20). This gave the title compoundas a colorless solid (60 mg, 82% of theory).

LC-MS (Method 6): R_(t)=2.42 min; MS (ESIpos): m/z (%)=489.0 (100)[M+H]⁺; MS (ESIneg): m/z (%)=487.0 (100) [M−H]⁻

¹H-NMR (400 MHz, DMSO-d₆): δ=1.20 (t, 3H), 1.80 (s, 3H), 2.68 (s, 3H),3.55 (m, 2H), 6.45 (s, 1H), 7.70-8.05 (m, 4H), 8.40 (m, 3H).

Example 129(4S)-4-[4-Cyano-2-(ethylsulfonyl)phenyl]-6-methyl-3-(methylsulfonyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile

The reaction was carried out under argon.(4S)-4-[4-Cyano-2-(ethylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile(71.2 mg, 150 μmol) was initially charged in dry THF (3 ml), and sodiumhydride (60% in mineral oil; 8.4 mg, 210 μmol; 1.4 eq.) was added at 0°C. The mixture was warmed to RT and stirred for 20 min. A solution ofmethanesulfonyl chloride (24.1 mg, 210 μmol; 1.4 eq.) in THF (1 ml) wasthen slowly added dropwise. After a reaction time of 20 h, the reactionmixture was concentrated and the crude product was purified bypreparative HPLC (column: Gromsil C-18 10 μm; mobile phase:acetonitrile/water+0.1% TFA 10:90→80:20). This gave the title compoundas a colorless solid (70 mg, 84% of theory).

LC-MS (Method 6): R_(t)=2.42 min; MS (ESIpos): m/z (%)=553.0 (100)[M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=1.25 (t, 3H), 1.80 (s, 3H), 3.40 (s, 3H),3.55 (m, 2H), 7.20 (s, 1H), 7.80-8.40 (m, 7H).

Example 130 Allyl(rac)-4-[4-cyano-24(2-hydroxyethyl)sulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The reaction was carried out under argon. Triethyl phosphate (1.43 g,7.9 mmol; 1.2 eq.) and diphosphorus pentoxide (0.745 g; 0.8 eq.) werestirred at 40° C. overnight. The mixture was then diluted with MTBE (35ml), and 3-[(2-hydroxyethyl)sulfonyl]-4-formylbenzonitrile (1.57 g, 6.6mmol), 1-[3-(trifluoromethyl)phenyl]urea (1.34 g, 6.6 mmol) and allylacetoacetate (1.4 g, 9.84 mmol; 1.5 eq.) were added. The mixture wasstirred under reflux for 2 h. The reaction mixture was then concentratedby distillative removal of MTBE and subsequently heated at 90° C. for afurther 5 h. For work-up, residual solvent was removed under reducedpressure and the residue was taken up in ethyl acetate (250 ml). Theorganic phase was washed with saturated sodium chloride solution (3×50ml), dried over solid sodium sulfate, filtered and concentrated underreduced pressure. The residue was subjected to flash chromatography onsilica gel (mobile phase: cyclohexane→cyclohexane/ethyl acetate 2:3).The title compound was obtained as a colorless solid (1.22 g, 23% oftheory).

LC-MS (Method 4): R_(t)=1.20 min; MS (ESIpos): m/z (%)=550.1 (100)[M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=2.15 (s, 3H), 3.54 (m, 2H), 3.85 (m, 2H),4.45 (m, 2H), 5.00 (d, 1H), 5.05 (d, 1H), 5.15 (t, 1H), 5.70 (m, 1H),6.30 (d, 1H), 7.05 (d, 1H), 7.70-7.85 (m, 4H), 8.10 (br. d, 1H), 8.25(m, 1H), 8.35 (m, 1H).

Example 131(rac)-4-[4-Cyano-2-((2-hydroxyethyl)sulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide

The reaction was carried out under argon.(rac)-4-[4-Cyano-2-((2-hydroxyethyl)sulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (910 mg, 1.79 mmol) and HATU (5 eq., 3396 mg, 8.9 mmol) wereinitially charged in dry DMF (20 ml) at 0° C., and ammonium chloride (5eq., 478 mg, 8.9 mmol) and DIEA (10 eq., 2309 mg, 17.9 mmol) were addedafter brief stirring (20 min). The mixture was stirred at RT for 16 h(HPLC control) and then concentrated under reduced pressure. The crudeproduct was purified by preparative HPLC (column: Gromsil C-18; mobilephase: acetonitrile/water+0.1% TFA 10:90→80:20). The title compound wasobtained as a solid (740 mg, 81% of theory).

LC-MS (Method 6): R_(t)=1.84 min; MS (ESIpos): m/z (%)=509.1 (100)[M+H]⁺; MS (ESIneg): m/z (%)=464.3 (100), 507.1 (50) [M−H]⁻

¹H-NMR (400 MHz, DMSO-d₆): δ=1.80 (s, 3H), 3.70 (m, 4H), 6.30 (s, 1H),7.10 (m, 1H), 7.25 (br. s, 1H), 7.45 (br. s, 1H), 7.65-7.80 (m, 4H),8.10 (d, 1H), 8.30 (m, 2H).

Example 132(rac)-4-[4-Cyano-2-((2-hydroxyethyl)sulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile

The reaction was carried out under argon.4-{2-[(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)sulfonyl]-4-cyanophenyl}-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile(550 mg, 0.909 mmol) was initially charged in dichloromethane (30 ml),trifluoroacetic acid (30 ml) was added and the mixture was stirred at RTfor 5 h (HPLC control). The mixture was then concentrated withoutheating, and the residue was taken up in dichloromethane (200 ml). Theorganic phase was washed with saturated sodium bicarbonate solution(2×50 ml) and with saturated sodium chloride solution (50 ml), driedover solid sodium sulfate, filtered and concentrated under reducedpressure. The oil obtained was taken up in a little acetonitrile, waterwas added and the mixture was lyophilized. The title compound wasobtained as a solid (450 mg, quant.).

LC-MS (Method 6): R_(t)=2.15 min; MS (ESIpos): m/z (%)=491.0 (100)[M+H]⁺; MS (ESIneg): m/z (%)=446.0 (100), 489.0 (40) [M−H]⁻.

Example 133(4S)-4-[4-Cyano-2-((2-hydroxyethyl)sulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile

(rac)-4-[4-Cyano-2-((2-hydroxyethyl)sulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile(0.13 g) was separated into the enantiomers by preparative HPLCchromatography on a chiral phase [column: Daicel Chiralpak IC, 5 μm;column dimensions: 250 mm×20 mm; sample preparation: solution inmethanol (10 ml); injection volume: 0.5 ml; mobile phase: MTBE/methanol7:3; flow rate: 15 ml/min; temperature: 30° C.; detection: 220 nm]. Thisgave 0.042 g (65% of theory; >99.5% ee) of the 4S enantiomer. Theenantiomeric excess (ee value) was determined chromatographically[column: Daicel Chiralpak IC, 5 μm; column dimensions: 250 mm×4.6 mm;mobile phase: MTBE/methanol 7:3; flow rate: 1 ml/min; detection: 220 nm;R=4.00 min (4R enantiomer: R_(t)=5.15 min)].

LC-MS (Method 5): R_(t)=1.72 min; MS (ESIpos): m/z (%)=491.1 (100)[M+H]⁺; MS (ESIneg): m/z (%)=446.1 (100), 489.2 (30) [M−H]⁻.

Example 134 Allyl(rac)-4-{4-cyano-2-[(1-methylethyl)sulfonyl]phenyl}-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The reaction was carried out under argon. Triethyl phosphate (1.049 g,5.76 mmol) and diphosphorus pentoxide (0.454 g) were stirred at 40° C.overnight. The mixture was then diluted with MTBE (25 ml), and4-formyl-3-[(1-methylethyl)sulfonyl]benzonitrile (0.759 g, 3.2 mmol),1-[3-(tri-fluoromethyl)phenyl]urea (0.653 g, 3.2 mmol) and allylacetoacetate (0.682 g, 4.8 mmol; 1.5 eq.) were added. The mixture wasstirred under reflux for 6 h. The reaction mixture was then concentratedby distillative removal of MTBE and subsequently heated at 90° C. for afurther 2 h. For work-up, residual solvent was removed under reducedpressure and the residue was suspended in MTBE (20 ml) and then filteredoff with suction. The solid was washed with MTBE (2×10 ml). This gave1.25 g (48% of theory) of the title compound.

LC-MS (Method 4): R_(t)=1.37 min; MS (ESIpos): m/z (%)=548.1 (100)[M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=1.13 (d, 3H), 1.40 (d, 3H), 2.15 (s, 3H),3.71 (m, 1H), 4.50 (m, 2H), 4.95 (d, 1H), 5.05 (d, 1H), 5.70 (m, 1H),6.15 (d, 1H), 6.80 (d, 1H), 7.70-7.85 (m, 4H), 8.15 (br. d, 1H), 8.30(m, 2H).

Example 135(rac)-4-{4-Cyano-2-[(1-methylethyl)sulfonyl]phenyl}-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide

The reaction was carried out under argon.(rac)-4-{4-Cyano-2-[(1-methylethyl)sulfonyl]phenyl}-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (1000 mg, 1.97 mmol) and HATU (3 eq., 2248 mg, 5.9 mmol) wereinitially charged in dry DMF (25 ml) at 0° C., and a 0.5 M solution ofammonia in dioxane (3 eq., 11.8 ml, 5.9 mmol) and DIEA (3 eq., 764 mg,5.9 mmol) were added after brief stirring (20 min). The mixture wasstirred at RT for 6 h (HPLC control) and then concentrated under reducedpressure. The crude product was purified by preparative HPLC (column:Gromsil C-18; mobile phase: acetonitrile/water+0.1% TFA 10:90→80:20).The title compound was obtained as a solid (750 mg, 75% of theory).

LC-MS (Method 5): R_(t)=1.61 min; MS (ESIpos): m/z (%)=507.2 (100)[M+H]⁺; MS (ESIneg): m/z (%)=505.2 (100) [M−H]⁻

¹H-NMR (400 MHz, DMSO-d₆): δ=1.07 (d, 3H), 1.35 (d, 3H), 1.80 (s, 3H),3.85 (m, 1H), 6.20 (s, 1H), 7.05 (d, 1H), 7.30 (br. s, 1H), 7.45 (br. s,1H), 7.65-7.80 (m, 4H), 8.15 (d, 1H), 8.25 (d, 1H), 8.35 (dd, 1H).

Example 136(rac)-4-{4-Cyano-2-[(1-methylethyl)sulfonyl]phenyl}-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile

The reaction was carried out under argon.(rac)-4-{4-Cyano-2-[(1-methylethyl)sulfonyl]phenyl}-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide(730 mg, 1.44 mmol) was initially charged in dry THF (35 ml),methoxycarbonylsulfamoyltriethylammonium hydroxide (Burgess reagent; 687mg, 2.88 mmol; 2 eq.) was added and the mixture was stirred at RT. After75 min, HPLC control showed complete conversion. Water (20 ml) was thenadded, the reaction mixture was concentrated and the residue was takenup in ethyl acetate (200 ml). The organic phase was washed withsaturated sodium chloride solution (3×30 ml), dried over solid sodiumsulfate, filtered and concentrated. The residue was subjected to flashchromatography on silica gel (mobile phase:cyclohexane→cyclohexane/ethyl acetate 1:1). The title compound wasobtained as a colorless solid (700 mg, 99% of theory).

LC-MS (Method 4): R_(t)=1.22 min; MS (ESIpos): m/z (%)=489.1 (100)[M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=1.20 (d, 3H), 1.30 (d, 3H), 1.80 (s, 3H),3.55 (m, 1H), 6.30 (s, 1H), 7.70-7.85 (m, 3H), 7.95 (br. s, 1H),8.30-8.40 (m, 4H).

Example 137(4S)-4-{4-Cyano-2-[(1-methylethyl)sulfonyl]phenyl}-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile

(rac)-4-{4-Cyano-2-[(1-methylethyl)sulfonyl]phenyl}-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile(0.70 g) was separated into the enantiomers by preparative HPLCchromatography on a chiral phase [column: Daicel Chiralpak IC, 5 μm;column dimensions: 250 mm×20 mm; sample preparation: solution inmethanol/acetonitrile (1:6, 35 ml); injection volume: 0.5 ml; mobilephase: MTBE/methanol 7:3; flow rate: 15 ml/min; temperature: 30° C.;detection: 220 nm]. This gave 0.334 g (95% of theory; >98.5% ee) of the4S enantiomer.

The enantiomeric excess (ee value) was determined chromatographically[column: Daicel Chiralpak IA, 5 μm; column dimensions: 250 mm×4.6 mm;mobile phase: MTBE/acetonitrile 7:3; flow rate: 1 ml/min; detection: 220nm; R=3.46 min (4R enantiomer: R_(t)=4.905 min)].

LC-MS (Method 5): R_(t)=1.97 min; MS (ESIpos): m/z (%)=489.2 (100)[M+H]⁺; MS (ESIneg): m/z (%)=444.2 (100), 487.2 (70) [M−H]⁻.

For the ¹H-NMR data, see the racemic compound (Example 136).

Example 138 Allyl(rac)-4-[4-cyano-2-(phenylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The reaction was carried out under argon. Triethyl phosphate (172 mg,0.947 mmol) and diphosphorus pentoxide (90 mg) were stirred at 40° C.overnight. The mixture was then diluted with MTBE (9.5 ml), and4-formyl-3-(phenylsulfonyl)benzonitrile (214 mg, 0.789 mmol),1-[3-(trifluoromethyl)phenyl]urea (0.161 g, 0.789 mmol) and allylacetoacetate (0.168 g, 1.18 mmol; 1.5 eq.) were added. The mixture wasstirred under reflux for 16 h. The reaction mixture was thenconcentrated by distillative removal of MTBE and subsequently heated at90° C. for a further 2 h. For work-up, residual solvent was removedunder reduced pressure and the residue was taken up in ethyl acetate(150 ml). The organic phase was washed with saturated sodium chloridesolution (2×30 ml), dried over solid sodium sulfate, filtered andconcentrated under reduced pressure. The crude product was purified bypreparative HPLC (column: Gromsil C-18; mobile phase:acetonitrile/water+0.1% TFA 10:90→90:10). The title compound wasobtained as a solid (230 mg, 33% of theory).

LC-MS (Method 4): R_(t)=1.40 min; MS (ESIpos): m/z (%)=582.1 (100)[M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=2.10 (s, 3H), 3.45 (m, 1H), 4.10 (m, 1H),4.50 (m, 2H), 4.75 (d, 1H), 5.15 (m, 1H), 6.15 (d, 1H), 6.95 (d, 1H),7.65-7.80 (m, 7H), 8.05 (br. d, 1H), 8.15 (d, 2H), 8.25 (dd, 1H), 8.60(d, 1H).

Example 139(rac)-4-{4-Cyano-2-[phenylsulfonyl]phenyl}-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide

The reaction was carried out under argon.(rac)-4-{4-Cyano-2-[phenylsulfonyl]phenyl}-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (166 mg, 0.307 mmol) and HATU (5 eq., 583 mg, 1.53 mmol) wereinitially charged in dry DMF (3.5 ml) at 0° C., and ammonium chloride (5eq., 82 mg, 1.53 mmol) [alternatively: 1.23 ml of a 0.5 M solution ofammonia in dioxane] and DIEA (10 eq., 369 mg, 3.07 mmol) were addedafter brief stirring (20 minutes). The mixture was stirred at RT for 6 h(HPLC control) and then concentrated under reduced pressure. The crudeproduct was purified by preparative HPLC (column: Gromsil C-18; mobilephase: acetonitrile/water+0.1% TFA 10:90→90:10). This gave the titlecompound as a solid (147 mg, 89% of theory).

LC-MS (Method 6): R_(t)=2.18 min; MS (ESIpos): m/z (%)=541.0 (100)[M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): δ=1.75 (s, 3H), 6.20 (s, 1H), 6.85 (d, 1H),7.05 (br. s, 1H), 7.30 (br. s, 1H), 7.60-7.80 (m, 7H), 8.15 (m, 3H),8.25 (d, 1H), 8.55 (s, 1H).

Example 140(rac)-4-{4-Cyano-2-[phenylsulfonyl]phenyl}-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile

The reaction was carried out under argon.(rac)-4-{4-Cyano-2-[phenylsulfonyl]phenyl}-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide(137 mg, 253 μmol) was initially charged in dry THF (8 ml),methoxycarbonylsulfamoyltriethylammonium hydroxide (Burgess reagent; 121mg, 507 μmol; 2 eq.) was added and the mixture was stirred at RT for 8 h(HPLC control). The reaction mixture was then concentrated under reducedpressure, and the residue was purified by preparative HPLC (column:Gromsil C-18; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10).This gave the title compound as a solid (106 mg, 80% of theory).

LC-MS (Method 5): R_(t)=2.07 min; MS (ESIpos): m/z (%)=523.1 (100)[M+H]⁺; MS (ESIneg): m/z (%)=478.1 (100), 521.2 (20) [M−H]⁻

¹H-NMR (400 MHz, DMSO-d₆): δ=1.75 (s, 3H), 6.35 (s, 1H), 7.65-8.35 (m,12H), 8.60 (s, 1H).

Example 141(4S)-4-{4-Cyano-2-[phenylsulfonyl]phenyl}-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile

(rac)-4-{4-Cyano-2-[phenylsulfonyl]phenyl}-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile(90 mg) was separated into the enantiomers by preparative HPLCchromatography on a chiral phase [column: Daicel Chiralpak IC, 5 μm;column dimensions: 250 mm×20 mm; sample preparation: solution inmethanol/acetonitrile (1:1, 18 ml); mobile phase: MTBE/methanol 7:3;flow rate: 15 ml/min; temperature: 30° C.; detection: 220 nm]. This gave39 mg (87% of theory; >97.5% ee) of the 4S enantiomer.

The enantiomeric excess (ee value) was determined chromatographically[column: Daicel Chiralpak IA, 5 μm; column dimensions: 250 mm×4.6 mm;mobile phase: MTBE/methanol 7:3; flow rate: 1 ml/min; detection: 220 nm;R=3.49 min (4R enantiomer: R=5.95 min)].

LC-MS (Method 6): R_(t)=2.53 min; MS (ESIpos): m/z (%)=523.2 (100)[M+H]⁺; MS (ESIneg): m/z (%)=478.1 (100), 521.2 (20) [M−H]⁻.

For the ¹H-NMR data, see the racemic compound (Example 140).

Example 142 2-Hydroxyethyl(4S)-4-[4-cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The reaction was carried out under argon.(4S)-4-[4-Cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (170 mg, 355 μmol; Example 5A) was initially charged in dry DMF (4ml), 2-bromoethanol (177 mg, 1.42 mmol; 4 eq.) and triethylamine (72 mg,709 μmol; 2 eq.) were added and the mixture was stirred at 70° C. for 10h. The reaction mixture was then concentrated under reduced pressure,and the residue was taken up in ethyl acetate (50 ml). The organic phasewas washed with saturated sodium bicarbonate solution (2×20 ml) andsaturated sodium chloride solution (20 ml), dried over solid sodiumsulfate, filtered and concentrated under reduced pressure. The crudeproduct was purified by preparative HPLC (column: Gromsil C-18; mobilephase: acetonitrile/water+0.1% TFA 10:90→90:10). This gave the titlecompound as a solid (175 mg, 94% of theory).

LC-MS (Method 5): R_(t)=1.74 min; MS (ESIpos): m/z (%)=524.1 (100)[M+H]⁺; MS (ESIneg): m/z (%)=522.2 (100) [M−H]⁻

¹H-NMR (400 MHz, DMSO-d₆): δ=2.15 (s, 3H), 3.35 (m, 2H), 3.50 (s, 3H),3.90 (m, 1H), 4.00 (m, 1H), 4.65 (br. s, 1H), 6.30 (s, 1H), 7.10 (d,1H), 7.70-7.85 (m, 4H), 8.10 (br. d, 1H), 8.25 (dd, 1H), 8.35 (d, 1H).

Example 143 Allyl(4S)-4-[4-cyano-2-(methylsulfonyl)phenyl]-6-methyl-3-(methylsulfonyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The reaction was carried out under argon. Allyl(4S)-4-[4-cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate(260 mg, 500 μmol) was initially charged in dry THF (10 ml), and sodiumhydride (60% in mineral oil; 28 mg, 700 μmol; 1.4 eq.) was added at 0°C. The mixture was warmed to RT and stirred for 20 min. A solution ofmethanesulfonyl chloride (80 mg, 700 μmol; 1.4 eq.) in THF (2 ml) wasthen slowly added dropwise. After a reaction time of 20 h, the reactionmixture was concentrated and the residue was subjected to flashchromatograpy on silica gel (mobile phase: cyclohexane→cyclohexane/ethylacetate 55:45). The title compound was obtained as a colorless solid(288 mg, 96% of theory).

LC-MS (Method 5): R_(t)=2.24 min; MS (ESIpos): m/z (%)=540.1 (100),598.1 (40) [M+H]⁺; MS (ESIneg): m/z (%)=475.1 (80), 596.1 (100) [M−H]⁻.

Example 144 2-Hydroxyethyl(4S)-4-[4-cyano-2-(methylsulfonyl)phenyl]-6-methyl-3-(methylsulfonyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The reaction was carried out under argon.(4S)-4-[4-Cyano-2-(methylsulfonyl)phenyl]-6-methyl-3-(methylsulfonyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (84 mg, 150 μmol) was initially charged in dry DMF (2 ml),2-bromoethanol (75 mg, 600 μmol; 4 eq.) and triethylamine (31 mg, 300μmol; 2 eq.) were added and the mixture was stirred at 70° C. for 8 h.The reaction mixture was then concentrated under reduced pressure, andthe residue was taken up in ethyl acetate (50 ml). The organic phase waswashed with saturated sodium bicarbonate solution (2×20 ml) andsaturated sodium chloride solution (20 ml), dried over solid sodiumsulfate, filtered and concentrated under reduced pressure. The crudeproduct was subjected to flash chromatography on silica gel (mobilephase: cyclohexane→cyclohexane/ethyl acetate 1:3). The title compoundwas obtained as a colorless solid (56 mg, 62% of theory).

LC-MS (Method 4): R_(t)=1.13 min; MS (ESIpos): m/z (%)=539.9 (100), 602(20) [M+H]⁺; MS (ESIneg): m/z (%)=479.0 (100), 600.0 (80) [M−H]⁻

¹H-NMR (400 MHz, DMSO-d₆): δ=1.75 (s, 3H), 3.40 (s, 3H), 3.50 (m, 2H),4.05 (m, 2H), 4.65 (t, 1H), 7.30 (s, 1H), 7.75-7.90 (m, 3H), 8.05 (m,2H), 8.25 (dd, 1H), 8.50 (d, 1H) [a methyl signal was obscured by thesolvent peak].

Example 145 Allyl(4S)-4-[4-cyano-2-(methylsulfonyl)phenyl]-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The reaction was carried out under argon. Allyl(4S)-4-[4-cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate(260 mg, 0.5 mmol) was initially charged in absolute THF (10 ml), and a1 M solution of lithium hexamethyldisilazide (LiHMDS) in THF (0.6 ml,600 μmol; 1.2 eq.) was added at −78° C. After 20 min of stirring,iodomethane (355 mg, 2.5 mmol; 5 eq.) was added, and the mixture wasstirred for 16 h with gradual warming from −78° C. to RT. The reactionmixture was then concentrated under reduced pressure, and the residuewas subjected to flash chromatography on silica gel (mobile phase:cyclohexane→cyclohexane/ethyl acetate 55:45). The title compound wasobtained as a colorless solid (157 mg, 59% of theory).

LC-MS (Method 5): R_(t)=2.30 min; MS (ESIpos): m/z (%)=534.1 (100)[M+H]⁺; MS (ESIneg): m/z (%)=532.2 (100) [M−H]⁻.

Example 146 2-Hydroxyethyl(4S)-4-[4-cyano-2-(methylsulfonyl)phenyl]-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate

The reaction was carried out under argon.(4S)-4-[4-Cyano-2-(methylsulfonyl)phenyl]-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid (74 mg, 150 μmol) was initially charged in dry DMF (2 ml),2-bromoethanol (75 mg, 600 μmol; 4 eq.) and triethylamine (31 mg, 300μmol; 2 eq.) were added and the mixture was stirred at 70° C. for 8 h.The reaction mixture was then concentrated under reduced pressure, andthe residue was taken up in ethyl acetate (50 ml). The organic phase waswashed with saturated sodium bicarbonate solution (2×20 ml) andsaturated sodium chloride solution (20 ml), dried over solid sodiumsulfate, filtered and concentrated under reduced pressure. The crudeproduct was subjected to flash chromatography on silica gel (mobilephase: cyclohexane→cyclohexane/ethyl acetate 1:3). Theproduct-containing fractions were combined and concentrated, the residuewas taken up in a little acetonitrile, water was added and the mixturewas lyophilized. The title compound was obtained as a colorless solid(63 mg, 78% of theory).

LC-MS (Method 4): R_(t)=1.13 min; MS (ESIpos): m/z (%)=538.1 (100)[M+H]⁺; MS (ESIneg): m/z (%)=536.2 (100) [M−H]⁻

¹H-NMR (400 MHz, DMSO-d₆): δ=2.05 (s, 3H), 2.75 (s, 3H), 3.50 (m, 2H),3.55 (s, 3H), 4.05 (m, 2H), 4.70 (t, 1H), 6.75 (s, 1H), 7.70-7.85 (m,3H), 7.95 (br. s, 1H), 8.15 (br. d, 1H), 8.25 (dd, 1H), 8.50 (d, 1H).

Example 147(4S)-4-{4-Cyano-2-[methylsulfinyl]phenyl}-6-methyl-3-(methylsulfonyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile

The reaction was carried out under argon.(4S)-4-{4-Cyano-2-[methylsulfinyl]phenyl}-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile(444 mg, 1 mmol) was initially charged in dry THF (10 ml), and sodiumhydride (60% in mineral oil; 56 mg, 1.4 mmol; 1.4 eq.) was added at 0°C. The mixture was warmed to RT and stirred for 20 min. A solution ofmethanesulfonyl chloride (160 mg, 1.4 mmol; 1.4 eq.) in THF (5 ml) wasthen slowly added dropwise. After a reaction time of 16 h, ammoniumchloride solution (50 ml) was added to the reaction mixture, and themixture was extracted with ethyl acetate (3×30 ml). The combined organicphases were dried over sodium sulfate, filtered and concentrated underreduced pressure. The residue was purified by preparative HPLC (column:Gromsil C-18; mobile phase: acetonitrile/water+0.1% TFA 10:90→80:20).This gave the title compound as a solid (210 mg, 40% of theory).

LC-MS (Method 4): R_(t)=1.15 min; MS (ESIpos): m/z (%)=523.0 (100)[M+H]⁺; MS (ESIneg): m/z (%)=441.1 (100), 521.0 (100) [M−H]⁻

¹H-NMR (400 MHz, DMSO-d₆): δ=1.80 (s, 3H), 2.70 (s, 3H), 3.30 (s, 3H),6.75 (s, 1H), 7.70-8.32 (m, 6H), 8.50 (s, 1H).

Example 148(4S)-4-{4-Cyano-2-[(cyclobutylmethyl)sulfonyl]phenyl}-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile

The reaction was carried out under argon. Sodium5-cyano-2-{(4S)-5-cyano-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidin-4-yl}benzenesulfinate(150 mg, 101 μmol; purity 32%) was suspended in DMF (1 ml).1-(Bromomethyl)cyclobutane (164.1 mg) was then added, and the mixturewas heated in a closed tube at 110° C. for 72 h. The mixture was thenfiltered, and the filtrate was concentrated under reduced pressure. Theresidue was purified by preparative HPLC (column: Gromsil C-18 10 μm;mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). The titlecompound was obtained as a solid (40.2 mg, 75% of theory).

LC-MS (Method 4): R_(t)=1.42 min; MS (ESIpos): m/z (%)=529.3 (100)[M+H]⁺; MS (ESIneg): m/z (%)=527.3 (100) [M−H]⁻

¹H-NMR (400 MHz, DMSO-d₆): δ=1.76-2.10 (m, 9H), 2.65 (s, 3H), 2.70 (m,1H), 3.65 (dd, 1H), 3.75 (dd, 1H), 6.45 (s, 1H), 7.70-8.40 (m, 7H).

Example 149(4S)-4-{4-Cyano-2-[(cyclopropylmethyl)sulfonyl]phenyl}-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile

The reaction was carried out under argon. Sodium5-cyano-2-{(4S)-5-cyano-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidin-4-yl}benzenesulfinate(100 mg, 67 μmol; purity 32%) was suspended in DMF (2000 μl).1-(Bromomethyl)cyclopropane (278 mg, 2.06 mmol) was then added, and themixture was heated in a closed tube at 130° C. overnight. Molecularsieve (4 Å), potassium iodide (110 mg, 0.66 mmol) and more1-(bromomethyl)cyclopropane (89 mg, 0.66 mmol) were then added, and thereaction mixture was once more heated in a closed tube at 100° C. for 6h. The mixture was then filtered, and the filtrate was concentratedunder reduced pressure. The residue was purified by preparative HPLC(column: Gromsil C-18 10 μm; mobile phase: acetonitrile/water+0.1% TFA10:90→90:10). The title compound was obtained as a solid (16.2 mg, 44%of theory).

LC-MS (Method 9): R_(t)=1.16 min; MS (ESIpos): m/z (%)=515.2 (100)[M+H]⁺; MS (ESIneg): m/z (%)=513.2 (80) [M−H]⁻

¹H-NMR (400 MHz, DMSO-d₆): δ=0.20 (m, 1H), 0.30 (m, 1H), 0.50 (m, 1H),0.60 (m, 1H), 1.00 (m, 1H), 1.80 (s, 3H), 2.70 (s, 3H), 3.45 (dd, 1H),3.60 (dd, 1H), 6.50 (s, 1H), 7.75-8.45 (m, 7H).

Example 150(4S)-4-{4-Cyano-2-[(3,3,3-trifluoropropyl)sulfonyl]phenyl}-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile

The reaction was carried out under argon. Sodium5-cyano-2-{(4S)-5-cyano-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidin-4-yl}benzenesulfinate(66 mg, 44 μmol; purity 32%) was suspended in DMF (600 μl).1,1,1-Trifluoro-3-iodopropane (144 mg, 643 μmol; 14.6 eq.) was thenadded, and the mixture was heated in a closed tube at 120° C. overnight.The mixture was then filtered, and the filtrate was concentrated underreduced pressure. The residue was purified by preparative HPLC (column:Gromsil C-18 10 μm; mobile phase: aceto-nitrile/water+0.1% TFA10:90→90:10). The title compound was obtained as a solid (7.4 mg, 30% oftheory).

LC-MS (Method 9): R_(t)=1.18 min; MS (ESIpos): m/z (%)=557.2 (100)[M+H]⁺; MS (ESIneg): m/z (%)=555.2 (80) [M−H]⁻

¹H-NMR (400 MHz, DMSO-d₆): δ=1.80 (s, 3H), 2.70 (s, 3H), 2.80 (m, 2H),3.90 (t, 2H), 6.45 (s, 1H), 7.65-8.40 (br. m, 5H), 8.45 (m, 1H), 8.55(s, 1H).

Example 151(4S)-4-{4-Cyano-2-[(trifluoromethyl)sulfonyl]phenyl}-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile

The reaction was carried out under argon. Tris(dimethylamino)sulfoniumdifluorotrimethylsilicate (TASF; 18.4 mg, 66.7 μmol; 1.1 eq.) and(trifluoromethyl)trimethylsilane (2 M solution in THF, 60.6 μl, 121μmol) were initially charged in THF (1.45 ml) at 0° C.5-Cyano-2-{(4S)-5-cyano-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidin-4-yl}benzenesulfonylchloride (30 mg, 60.6 μmol) was added, and the mixture was stirred at RTovernight. More tris(dimethylamino)sulfonium difluorotrimethylsilicate(TASF; 16.7 mg, 60.6 μmol; 1.0 eq.) and (trifluoromethyl)trimethylsilane(2 M solution in THF, 65 μl, 130 μmol) were then added at 0° C., and themixture was again stirred for 15 h with gradual warming to RT. Themixture was then filtered, and the filtrate was concentrated underreduced pressure. The residue was purified by preparative HPLC (column:Gromsil C-18 10 μm; mobile phase: acetonitrile/water+0.1% TFA10:90→90:10). The title compound was obtained as a solid (3.3 mg, 10% oftheory).

LC-MS (Method 9): R_(t)=1.19 min; MS (ESIpos): m/z (%)=529.2 (100)[M+H]⁺; MS (ESIneg): m/z (%)=527.1 (80) [M−H]⁻.

¹H-NMR (400 MHz, DMSO-d₆): δ=1.80 (s, 3H), 2.65 (s, 3H), 6.25 (s, 1H),7.75-8.55 (m, 5H), 8.65 (dd, 1H), 8.80 (s, 1H).

Example 152(4S)-4-[2-(Benzylsulfonyl)-4-cyanophenyl]-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile

The reaction was carried out under argon. Sodium5-cyano-2-{(4S)-5-cyano-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidin-4-yl}benzenesulfinate(150 mg, 101 μmol; purity 32%) was suspended in DMF (1 ml). Benzylbromide (173 mg, 1.01 mmol; 10 eq.) was then added, and the mixture washeated in a closed tube at 110° C. for 24 h. Molecular sieve (4 Å),potassium iodide (110 mg, 0.66 mmol) and further benzyl bromide (173 mg,1.01 mmol; 10 eq.) were then added, and the reaction mixture was againheated in a closed tube at 100° C. for 6 h. The mixture was thenfiltered, and the filtrate was concentrated under reduced pressure. Theresidue was purified by preparative HPLC (column: Gromsil C-18 10 μm;mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). The titlecompound was obtained as a solid (49.3 mg, 89% of theory).

LC-MS (Method 9): R_(t)=1.22 min; MS (ESIpos): m/z (%)=551.3 (100)[M+H]⁺; MS (ESIneg): m/z (%)=549.2 (100) [M−H]⁻

¹H-NMR (400 MHz, DMSO-d₆): δ=1.80 (s, 3H), 2.45 (s, 3H), 4.90 (q, 2H),6.55 (s, 1H), 7.30-7.40 (m, 5H), 7.70-8.40 (m, 7H).

Example 153(4S)-4-{4-Cyano-2-[(2-methoxyethyl)sulfonyl]phenyl}-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile

The reaction was carried out under argon. Sodium5-cyano-2-{(4S)-5-cyano-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidin-4-yl}benzenesulfinate(100 mg, 73 μmol; purity 32%) was suspended in DMF (0.5 ml).2-Bromoethyl methyl ether (148 mg, 1.06 mmol) was then added, and themixture was heated in a closed tube at 115° C. for 15 h. The mixture wasthen filtered, and the filtrate was concentrated under reduced pressure.The residue was purified by preparative HPLC (column: Gromsil C-18 10μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). The titlecompound was obtained as a solid (27.3 mg, 73% of theory).

LC-MS (Method 9): R_(t)=1.11 min; MS (ESIpos): m/z (%)=519.2 (100)[M+H]⁺; MS (ESIneg): m/z (%)=517.2 (100) [M−H]⁻

¹H-NMR (400 MHz, DMSO-d₆): δ=1.80 (s, 3H), 2.70 (s, 3H), 3.15 (s, 3H),3.70-3.87 (m, 4H), 6.45 (s, 1H), 7.30-8.40 (m, 6H), 8.45 (m, 1H).

Example 154(4S)-4-{4-Cyano-2-[(1,3-thiazol-4-ylmethyl)sulfonyl]phenyl}-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile

The reaction was carried out under argon. 4-(Chloromethyl)thiazolehydrochloride (86 mg, 505 μmol; 5.0 eq.), sodium5-cyano-2-{(4S)-5-cyano-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidin-4-yl}benzenesulfinate(150 mg, 101 μmol; purity 32%), potassium carbonate (77 mg, 556 μmol;5.5 eq.), potassium iodide (84 mg, 505 μmol; 5.0 eq.) and 18-crown-6(13.4 mg, 51 μmol; 0.5 eq.) were suspended in DMF (3 ml). The mixturewas then heated in a closed tube at 110° C. for 15 h. Molecular sieve (4Å), potassium iodide (84 mg, 505 μmol; 5.0 eq.) and further4-(chloromethyl)thiazole hydrochloride (86 mg, 505 μmol; 5.0 eq.) werethen added, and the reaction mixture was again heated in a closed tubeat 100° C. for 2 h. The mixture was then filtered, and the filtrate wasconcentrated under reduced pressure. The residue was purified bypreparative

HPLC (column: Gromsil C-18 10 μm; mobile phase: acetonitrile/water+0.1%TFA 10:90→90:10). The title compound was obtained as a solid (37 mg, 66%of theory).

LC-MS (Method 4): R_(t)=1.25 min; MS (ESIpos): m/z (%)=558.1 (100)[M+H]⁺; MS (ESIneg): m/z (%)=492.3 (100), 557.0 (100) [M−H]⁻

¹H-NMR (400 MHz, DMSO-d₆): δ=1.80 (s, 3H), 2.60 (s, 3H), 5.15 (m, 2H),6.50 (s, 1H), 7.70-8.40 (br. m, 8H), 9.0 (s, 1H).

Example 155(4S)-4-[2-(Cyclobutylsulfonyl)-4-cyanophenyl]-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile

Under argon, sodium5-cyano-2-{(4S)-5-cyano-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidin-4-yl}benzenesulfinate(150 mg, 65 μmol; purity about 21%) was suspended in a pressure-proofglass tube in DMF (1 ml). Molecular sieve (4 Å, 20 mg) andbromocyclobutane (100 μl, 1088 μmol, 16.7 eq.) were added. The sealedtube was heated at 115° C. for 15 h. The reaction mixture was thenfiltered, and the filtrate was concentrated under reduced pressure. Theresidue was purified by preparative HPLC (Gromsil C18 column; mobilephase: acetonitrile/water+0.1% TFA). After lyophilization, the titlecompound was obtained as a solid (15.5 mg, purity according to LC-MS90%, 41% of theory).

LC-MS (Method 9): R_(t)=1.20 min; MS (ESIpos): m/z (%)=515.3 (100)[M+H]⁺; MS (ESIneg): m/z (%)=513.2 (100) [M−H]⁻.

Example 156(4S)-4-{4-Cyano-2-[(trifluoromethyl)sulfanyl]phenyl}-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile

Under argon,(4S)-4-(4-cyano-2-sulfanylphenyl)-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile(45 mg, purity 50%, 53 μmol) was dissolved in dichloromethane (1 ml). At−78° C., 3,3-dimethyl-1-(trifluoromethyl)-1,3-dihydro-1λ³,2-benziodoxole(26 mg, 79 μmol; 1.5 eq.) was added, and the mixture was stirred for 2h. The reaction solution was then concentrated under reduced pressure,and the residue was purified by preparative HPLC (Kromasil C18 column,20×50 mm; mobile phase: acetonitrile/water+0.1% TFA). Afterlyophilization, the title compound was obtained as a solid (11.4 mg, 44%of theory).

LC-MS (Method 9): R_(t)=1.24 min; MS (ESIpos): m/z (%)=497.3 (100)[M+H]⁺; MS (ESIneg): m/z (%)=495.2 (100) [M−H]⁻

¹H-NMR (400 MHz, DMSO-d₆): δ=1.75 (s, 3H), 2.70 (s, 3H), 6.00 (s, 1H),7.75 (m, 2H), 7.85 (m, 2H), 8.05 (br. s, 1H), 8.25 (m, 1H), 8.45 (s,1H).

B. ASSESSMENT OF THE PHARMACOLOGICAL ACTIVITY

The pharmacological effect of the compounds of the invention can beshown in the assays described below:

ABBREVIATIONS

AMC 7-amido-4-methylcoumarin BNP brain natriuretic peptide BSA bovineserum albumin HEPES N-(2-hydroxyethyl)piperazine-N′-2-ethanesulfonicacid HNE humane neutrophil elastase IC inhibitory concentration MeOSucmethoxysuccinyl NADP nicotinamide adenine dinucleotide phosphate v/vvolume to volume ratio (of a solution) w/v weight to volume ratio (of asolution)

B-1. In Vitro HNE Inhibition Assay

The potency of the compounds of the invention is ascertained in an invitro inhibition assay. The HNE-mediated amidolytic cleavage of asuitable peptide substrate leads in this connection to an increase inthe fluorescent light. The signal intensity of the fluorescent light isdirectly proportional to the enzyme activity. The effectiveconcentration of a test compound at which half the enzyme is inhibited(50% signal intensity of the fluorescent light) is indicated as IC₅₀.

Procedure:

Enzyme (80 pM HNE; from Serva, Heidelberg) and substrate (20 μMMeOSuc-Ala-Ala-Pro-Val-AMC; from Bachem, Weil am Rhein) are incubated inan assay volume of in total 50 μl of assay buffer (0.1 M HEPES pH 7.4,0.5 M NaCl, 0.1% w/v BSA, 1% v/v DMSO) in a 384-well microtiter plate inthe presence and absence of the test substance at 37° C. for 2 hours.The intensity of the fluorescent light from the assay mixtures ismeasured (Ex. 380 nm, Em. 460 nm). The IC₅₀ values are determined byplotting the intensity of the fluorescent light against the activesubstance concentration.

Representative IC₅₀ values for the compounds of the invention at an HNEconcentration of 80 pM are shown in table A below:

TABLE A Inhibition of human neutrophil elastase (HNE) Exemplaryembodiment No. IC₅₀ [nM]  2 10.0  6 0.5  10 <0.3  12 <0.3  14 <0.3  18<0.3  20 1.9  22 0.45  27 <0.3  32 <0.3  33 <0.3  36 <0.3  41 <0.3  430.3 (Diastereomer 1)  50 1.6  51 <0.3  55 <0.3  69 0.9  80 <0.3  85 <0.3 91 <0.3  96 <0.3 103 <0.3 116 <0.3 120 <0.3 128 <0.3 132 1.1 141 <0.3144 <0.3

B-2. Animal Model of Pulmonary Arterial Hypertension

The monocrotaline-induced pulmonary hypertension in rats is a widelyused animal model of pulmonary arterial hypertension. The pyrrolizidinealkaloid monocrotaline is metabolized after subcutaneous injection tothe toxic monocrotalinepyrrole in the liver and leads within a few daysto endothelial damage in the pulmonary circulation, followed by aremodeling of the small pulmonary arteries (media hypertrophy, de novomuscularization). A single subcutaneous injection is sufficient toinduce pronounced pulmonary hypertension in rats within 4 weeks [Cowanet al., Nature Med. 6, 698-702 (2000)].

Male Sprague-Dawley rats are used for the model. On day 0, the animalsreceive a subcutaneous injection of 60 mg/kg monocrotaline. Treatment ofthe animals begins no earlier than 14 days after the monocrotalineinjection and extends over a period of at least 14 days. At the end ofthe study, the animals undergo hemodynamic investigations, and thearterial and central venous oxygen saturation are determined. For thehemodynamic measurement, the rats are initially anesthetized withpentobarbital (60 mg/kg). The animals are then tracheotomized andartificially ventilated (rate: 60 breaths/min; inspiration to expirationratio: 50:50; positive end-expiratory pressure: 1 cm H₂O; tidal volume:10 ml/kg of body weight; FIO₂: 0.5). The anesthesia is maintained byisoflurane inhalation anesthesia. The systemic blood pressure isdetermined in the left carotid artery using a Millar microtip catheter.A polyethylene catheter is advanced through the right jugular vein intothe right ventricle to determine the right ventricular pressure. Thecardiac output is determined by thermodilution. Following thehemodynamics, the heart is removed and the ratio of right to leftventricle including septum is determined. In addition, plasma samplesare obtained to determine biomarkers (for example proBNP) and plasmasubstance levels.

B-3. Animal Model of Acute Lung Failure

Elastase-induced lung failure in mice, rats or hamsters is a widely usedanimal model of acute lung failure (also: “acute lung injury”, “acuterespiratory distress syndrome”)

[Tremblay et al., Chest 121, 582-588 (2002); Kuraki et al., Am. J. Resp.Grit. Care Med. 166, 596-500 (2002)]. The animals are treated 1 hourprior to orotracheal instillation of human neutrophil elastase (HNE). 2hours after orotracheal HNE instillation, a bronchoalveolar lavage iscarried out, and the hemoglobin content and the differential cellpicture of the lavage are determined.

B-4. Animal Model of Pulmonary Emphysema

Elastase-induced pulmonary emphysema in mice, rats or hamsters is awidely used animal model of pulmonary emphysema [Sawada et al., Exp.Lung Res. 33, 277-288 (2007)]. The animals receive an orotrachealinstillation of porcine pancreas elastase. The treatment of the animalsstarts at the day of the instillation of the porcine pancreas elastaseand extends over a period of 3 weeks. At the end of the study, thepulmonary compliance is determined, and an alveolar morphometry iscarried out.

B-5. CYP Inhibition Assay

The ability of substances to be able to inhibit CYP1A2, CYP2C9, CYP2D6and CYP3A4 in humans is investigated with pooled human liver microsomesas enzyme source in the presence of standard substrates (see below)which form CYP-specific metabolites. The inhibitory effects areinvestigated with six different concentrations of the test compounds[2.8, 5.6, 8.3, 16.7, 20 (or 25) and 50 μM], compared with the extent ofthe CYP-specific metabolite formation of the standard substrates in theabsence of the test compounds, and the corresponding IC₅₀ values arecalculated. A standard inhibitor which specifically inhibits a singleCYP isoform is always included in the incubation in order to make theresults comparable between different series.

Procedure:

Incubation of phenacetin, diclofenac, tolbutamide, dextromethorphan ormidazolam with human liver microsomes in the presence of in each casesix different concentrations of a test compound (as potential inhibitor)is carried out on a work station (Tecan, Genesis, Crailsheim, Germany).Standard incubation mixtures comprise 1.3 mM NADP, 3.3 mM MgCl₂×6H₂O,3.3 mM glucose 6-phosphate, glucose 6-phosphate dehydrogenase (0.4 U/ml)and 100 mM phosphate buffer (pH 7.4) in a total volume of 200 μl. Testcompounds are preferably dissolved in acetonitrile. 96-well plates areincubated with pooled human liver microsomes at 37° C. for a definedtime. The reactions are stopped by adding 100 μl of acetonitrile inwhich a suitable internal standard is always present. Precipitatedproteins are removed by centrifugation, and the supernatants arecombined and analyzed by LC-MS/MS.

B-6. Hepatocyte Assay to Determine the Metabolic Stability

The metabolic stability of test compounds in the presence of hepatocytesis determined by incubating the compounds with low concentrations(preferably below or around 1 μM) and with low cell counts (preferably1*10⁶ cells/ml) in order to ensure as far as possible linear kineticconditions in the experiment. Seven samples of the incubation solutionare taken in a fixed time pattern for the LD-MS analysis in order todetermine the half-life (i.e. the degradation) of the compound in eachcase. Various clearance parameters (CL) and F_(max) values arecalculated from this half-life (see below).

The C₁ and F_(max) values represent a measure of the phase 1 and phase 2metabolism of the compounds in the hepatocytes. In order to minimize theinfluence of the organic solvent on the enzymes in the incubationmixtures, this concentration is generally limited to 1% (acetonitrile)or 0.1% (DMSO).

A cell count for hepatocytes in the liver of 1.1*10⁸ cells/g of liver isused for calculation for all species and breeds. CL parameterscalculated on the basis of half-lives extending substantially beyond theincubation time (normally 90 minutes) can be regarded only as roughguidelines.

The calculated parameters and their meaning are:

F_(max) well-stirred maximum possible bioavailability after oral [%]administration Calculation: (1 − CL_(blood) well-stirred/QH) * 100CL_(blood) well-stirred calculated blood clearance (well stirred model)[L/(h * kg)] Calculation: (QH * CL′_(intrinsic))/(QH + CL′_(intrinsic))CL′_(intrinsic) maximum ability of the liver (of the hepatocytes) to[ml/(min * kg)] metabolize a compound (on the assumption that thehepatic blood flow is not rate-limiting) Calculation:CL′_(intrinsic, apparent) * species-specific hepatocyte count [1.1 *10⁸/g of liver] * species-specific liver weight [g/kg]CL′_(intrinsic, apparent) normalizes the elimination constant bydividing it by [ml/(min*mg)] the hepatocyte cell count x (x * 10⁶/ml)employed Calculation: k_(el) [1/min]/(cell count [x * 10⁶]/incubationvolumes [ml]) (QH = species-specific hepatic blood flow).

Representative values for the compounds according to the invention fromthis assay after incubation of the compounds with rat hepatocytes areshown in Table B below:

TABLE B calculated blood clearance and bioavailability after incubationwith rat hepatocytes Exemplary embodiment CL_(blood) F_(max) No. [L/(h *kg)] [%]  5 0.0 100  6 0.2 96  10 1.5 65  12 1.7 59  22 0.2 95  25 0.393  27 0.4 91  29 0.4 90  31 0.4 91  32 0.1 97  33 0.6 87  36 0.4 89  380.2 96  43 1.3 69 (diastereomer 1)  91 0.7 83  92 0.7 83 116 0.4 91 1170.1 97 118 0.6 86 123 1.0 75 127 0.2 94 128 0.9 78 129 0.9 79 144 1.2 72

C. EXEMPLARY EMBODIMENTS OF PHARMACEUTICAL COMPOSITIONS

The compounds of the invention can be converted into pharmaceuticalpreparations in the following ways:

Tablet: Composition:

100 mg of the compound of the invention, 50 mg of lactose (monohydrate),50 mg of corn starch (native), 10 mg of polyvinylpyrrolidone (PVP 25)(from BASF, Ludwigshafen, Germany) and 2 mg of magnesium stearate.Tablet weight 212 mg, diameter 8 mm, radius of curvature 12 mm.

Production:

The mixture of compound of the invention, lactose and starch isgranulated with a 5% strength solution (m/m) of the PVP in water. Thegranules are mixed with the magnesium stearate for 5 minutes afterdrying. This mixture is compressed with a conventional tablet press (seeabove for format of the tablet). A guideline compressive force for thecompression is 15 kN.

Suspension which can be administered orally:

Composition:

1000 mg of the compound of the invention, 1000 mg of ethanol (96%), 400mg of Rhodigel® (xanthan gum from FMC, Pennsylvania, USA) and 99 g ofwater. 10 ml of oral suspension correspond to a single dose of 100 mg ofthe compound of the invention.

Production:

The Rhodigel is suspended in ethanol, and the compound of the inventionis added to the suspension. The water is added while stirring. Themixture is stirred for about 6 h until the swelling of the Rhodigel iscomplete.

Solution which can be administered orally:

Composition:

500 mg of the compound of the invention, 2.5 g of polysorbate and 97 gof polyethylene glycol 400.20 g of oral solution correspond to a singledose of 100 mg of the compound according to the invention.

Production:

The compound of the invention is suspended in the mixture ofpolyethylene glycol and polysorbate with stirring. The stirring processis continued until the compound according to the invention hascompletely dissolved.

i.v. Solution:

The compound of the invention is dissolved in a concentration below thesaturation solubility in a physiologically tolerated solvent (e.g.isotonic saline solution, 5% glucose solution and/or 30% PEG 400solution). The solution is sterilized by filtration and used to fillsterile and pyrogen-free injection containers.

1. A compound of the formula (I)

in which A and E both represent C—R⁷ or one of the two ring members Aand E represents N and the other represents C—R⁷, in which R⁷ representsin each case hydrogen, fluorine or chlorine, Z represents O or S, nrepresents the number 0, 1 or 2, R¹ represents (C₁-C₆)-alkyl which maybe substituted by hydroxyl, (C₁-C₄)-alkoxy, amino, mono- ordi-(C₁-C₄)-alkylamino, hydroxycarbonyl, aminocarbonyl,(C₃-C₆)-cycloalkyl, phenyl or 5- or 6-membered heteroaryl or up to fivetimes by fluorine, or represents (C₂-C₆)-alkenyl, (C₃-C₆)-cycloalkyl,phenyl or 5- or 6-membered heteroaryl, where the (C₃-C₆)-cycloalkylgroups mentioned may be substituted up to two times by identical ordifferent substituents from the group consisting of (C₁-C₄)-alkyl,hydroxyl and (C₁-C₄)-alkoxy and the phenyl and heteroaryl groupsmentioned may be substituted up to two times by identical or differentsubstituents from the group consisting of fluorine, chlorine, cyano,(C₁-C₄)-alkyl, difluoromethyl, trifluoromethyl, (C₁-C₄)-alkoxy,difluoromethoxy and trifluoromethoxy, R² represents hydrogen, fluorineor chlorine, R³ represents cyano or a group of the formula —C(═O)—R⁸,—C(═O)—O—R⁸, —C(═O)—NH₂ or —C(═O)—NH—R⁸, in which R⁸ represents(C₁-C₆)-alkyl, (C₃-C₆)-alkenyl or (C₃-C₆)-cycloalkyl, where(C₁-C₆)-alkyl and (C₃-C₆)-cycloalkyl for their part may be substitutedup to two times by identical or different substituents from the groupconsisting of hydroxyl, (C₁-C₄)-alkoxy, hydroxycarbonyl,(C₁-C₄)-alkoxycarbonyl, amino, mono- and di-(C₁-C₄)-alkylamino and in(C₁-C₆)-alkyl and (C₃-C₆)-cycloalkyl in each case one CH₂ group may bereplaced by an oxygen atom, if this results in a chemically stablecompound, R⁴ represents methyl or ethyl or R³ and R⁴ are attached to oneanother and together form a fused group of the formula

in which * denotes the point of attachment to the 5-position, shown informula (I), of the dihydropyrimidine ring and ** denotes the point ofattachment to the 6-position, shown in formula (I), of thedihydropyrimidine ring and R⁹ represents hydrogen, (C₁-C₆)-alkyl or(C₃-C₆)-cycloalkyl, where (C₁-C₆)-alkyl may be substituted by hydroxyl,(C₁-C₄)-alkoxy, aminocarbonyl, aminocarbonylamino, (C₁-C₄)-acylamino or(C₃-C₆)-cycloalkyl, R⁵ represents hydrogen or (C₁-C₆)-alkyl which may besubstituted by cyano, hydroxyl, (C₁-C₄)-alkoxy, amino, mono- ordi-(C₁-C₄)-alkylamino or (C₃-C₆)-cycloalkyl or up to three times byfluorine, or represents phenyl, pyridyl or pyrimidinyl, where phenyl,pyridyl and pyrimidinyl for their part may be substituted up to twotimes by identical or different substituents from the group consistingof fluorine, chlorine, cyano, (C₁-C₄)-alkyl, trifluoromethyl,(C₁-C₄)-alkoxy and trifluoromethoxy, or R⁵ represents a group of theformula —C(═O)—O—R¹⁰, -L¹—C(═O)—O—R¹¹, -L²-C(═O)—NR¹²R¹³,-L²-SO₂—NR¹²R¹³, -L²-C(═O)—NR¹⁴—NR¹²R¹³ or -L²-SO₂—R¹⁵, in which L¹represents (C₁-C₆)-alkanediyl, L² represents a bond or(C₁-C₆)-alkanediyl, R¹⁰ represents (C₁-C₆)-alkyl which may besubstituted by (C₃-C₆)-cycloalkyl or phenyl, R¹¹ represents hydrogen or(C₁-C₆)-alkyl which may be substituted by (C₃-C₆)-cycloalkyl or phenyl,R¹² and R¹³ are identical or different and independently of one anotherrepresent hydrogen, (C₁-C₆)-alkyl, (C₃-C₆)-cycloalkyl or 4- to6-membered heterocyclyl, where (C₁-C₆)-alkyl, (C₃-C₆)-cycloalkyl and 4-to 6-membered heterocyclyl for their part may be substituted up to twotimes by identical or different substituents from the group consistingof fluorine, hydroxyl, (C₁-C₄)-alkoxy, oxo, amino, mono- ordi-(C₁-C₄)-alkylamino, hydroxycarbonyl, (C₁-C₄)-alkoxycarbonyl andaminocarbonyl and in (C₁-C₆)-alkyl a CH₂ group may be replaced by anoxygen atom, if this results in a chemically stable compound, and(C₃-C₆)-cycloalkyl and 4- to 6-membered heterocyclyl may additionally besubstituted up to two times by identical or different (C₁-C₄)-alkylradicals, which for their part may be substituted by hydroxyl,(C₁-C₄)-alkoxy or hydroxycarbonyl, or R¹² and R¹³ together with thenitrogen atom to which they are attached form a 4- to 6-memberedheterocycle which may contain a further ring heteroatom from the groupconsisting of N, O, S, SO and SO₂ and which may be substituted up to twotimes by identical or different substituents from the group consistingof (C₁-C₄)-alkyl, hydroxyl, (C₁-C₄)-alkoxy, oxo, amino, mono- ordi-(C₁-C₄)-alkylamino, hydroxycarbonyl, aminocarbonyl,(C₃-C₆)-cycloalkyl, 4- to 6-membered heterocyclyl and 5- or 6-memberedheteroaryl, where (C₁-C₄)-alkyl for its part may be substituted byhydroxyl, (C₁-C₄)-alkoxy or hydroxycarbonyl, R¹⁴ represents hydrogen or(C₁-C₄)-alkyl and R¹⁵ represents (C₁-C₆)-alkyl, (C₃-C₆)-cycloalkyl,phenyl or 5- or 6-membered heteroaryl, where (C₁-C₆)-alkyl may besubstituted by chlorine, hydroxyl, (C₁-C₄)-alkoxy, mono- ordi-(C₁-C₄)-alkylamino or (C₃-C₆)-cycloalkyl or up to three times byfluorine and phenyl and 5- or 6-membered heteroaryl for their part maybe substituted up to two times by identical or different substituentsfrom the group consisting of fluorine, chlorine, cyano, (C₁-C₄)-alkyl,difluoromethyl, trifluoromethyl, (C₁-C₄)-alkoxy and trifluoromethoxy,and R⁶ represents hydrogen, fluorine or chlorine, or a salt thereof. 2.The compound of the formula (I) as claimed in claim 1, in which A and Eboth represent C—R⁷ or one of the two ring members A and E represents Nand the other represents C—R⁷, in which R⁷ represents in each casehydrogen, fluorine or chlorine, Z represents O or S, n represents thenumber 0, 1 or 2, R¹ represents (C₁-C₆)-alkyl which may be substitutedby hydroxyl, (C₁-C₄)-alkoxy, amino, mono- or di-(C₁-C₄)-alkylamino,hydroxycarbonyl, aminocarbonyl, (C₃-C₆)-cycloalkyl or phenyl, orrepresents (C₂-C₆)-alkenyl, (C₃-C₆)-cycloalkyl or phenyl, where the(C₃-C₆)-cycloalkyl groups mentioned may be substituted up to two timesby identical or different substituents from the group consisting of(C₁-C₄)-alkyl, hydroxyl and (C₁-C₄)-alkoxy and the phenyl groupsmentioned may be substituted up to two times by identical or differentsubstituents from the group consisting of fluorine, chlorine, cyano,(C₁-C₄)-alkyl, difluoromethyl, trifluoromethyl, (C₁-C₄)-alkoxy,difluoromethoxy and trifluoromethoxy, R² represents hydrogen, fluorineor chlorine, R³ represents cyano or a group of the formula —C(═O)—R⁸,—C(═O)—O—R⁸, —C(═O)—NH₂ or —C(═O)—NH—R⁸, in which R⁸ represents(C₁-C₆)-alkyl, (C₃-C₆)-alkenyl or (C₃-C₆)-cycloalkyl, where(C₁-C₆)-alkyl and (C₃-C₆)-cycloalkyl for their part may be substitutedup to two times by identical or different substituents from the groupconsisting of hydroxyl, (C₁-C₄)-alkoxy, hydroxycarbonyl,(C₁-C₄)-alkoxycarbonyl, amino, mono- and di-(C₁-C₄)-alkylamino and in(C₁-C₆)-alkyl and (C₃-C₆)-cycloalkyl in each case one CH₂ group may bereplaced by an oxygen atom, if this results in a chemically stablecompound, R⁴ represents methyl or ethyl or R³ and R⁴ are attached to oneanother and together form a fused group of the formula

in which * denotes the point of attachment to the 5-position, shown informula (I), of the dihydropyrimidine ring and ** denotes the point ofattachment to the 6-position, shown in formula (I), of thedihydropyrimidine ring and R⁹ represents hydrogen, (C₁-C₆)-alkyl or(C₃-C₆)-cycloalkyl, where (C₁-C₆)-alkyl may be substituted by hydroxyl,(C₁-C₄)-alkoxy, aminocarbonyl, (C₁-C₄)-acylamino or (C₃-C₆)-cycloalkyl,R⁵ represents hydrogen or (C₁-C₆)-alkyl which may be substituted up tothree times by fluorine, or represents phenyl, pyridyl or pyrimidinyl,where phenyl, pyridyl and pyrimidinyl for their part may be substitutedup to two times by identical or different substituents from the groupconsisting of fluorine, chlorine, cyano, (C₁-C₄)-alkyl, trifluoromethyl,(C₁-C₄)-alkoxy and trifluoromethoxy, or R⁵ represents a group of theformula —C(═O)—O—R¹⁰, -L¹—C(═O)—O—R¹¹, -L²-C(═O)—NR¹²R¹³,-L²-SO₂—NR¹²R¹³, -L²-C(═O)—NR¹⁴—NR¹²R¹³ or -L²-SO₂—R¹⁵, in which L¹represents (C₁-C₆)-alkanediyl, L² represents a bond or(C₁-C₆)-alkanediyl, R¹⁰ represents (C₁-C₆)-alkyl, R¹¹ representshydrogen or (C₁-C₆)-alkyl, R¹² and R¹³ are identical or different andindependently of one another represent hydrogen, (C₁-C₆)-alkyl,(C₃-C₆)-cycloalkyl or 4- to 6-membered heterocyclyl, where(C₁-C₆)-alkyl, (C₃-C₆)-cycloalkyl and 4- to 6-membered heterocyclyl fortheir part may be substituted up to two times by identical or differentsubstituents from the group consisting of fluorine, hydroxyl,(C₁-C₄)-alkoxy, oxo, amino, mono- or di-(C₁-C₄)-alkylamino,hydroxycarbonyl, (C₁-C₄)-alkoxycarbonyl and aminocarbonyl and in(C₁-C₆)-alkyl a CH₂ group may be replaced by an oxygen atom, if thisresults in a chemically stable compound, or R¹² and R¹³ together withthe nitrogen atom to which they are attached form a 4- to 6-memberedheterocycle which may contain a further ring heteroatom from the groupconsisting of N, O, S, SO and SO₂ and may be substituted up to two timesby identical or different substituents from the group consisting of(C₁-C₄)-alkyl, hydroxyl, (C₁-C₄)-alkoxy, oxo, amino, mono- anddi-(C₁-C₄)-alkylamino, where (C₁-C₄)-alkyl for its part may besubstituted by hydroxyl or (C₁-C₄)-alkoxy, R¹⁴ represents hydrogen or(C₁-C₄)-alkyl and R¹⁵ represents (C₁-C₆)-alkyl, (C₃-C₆)-cycloalkyl,phenyl or 5- or 6-membered heteroaryl, where (C₁-C₆)-alkyl may besubstituted by fluorine, chlorine, hydroxyl, (C₁-C₄)-alkoxy, mono- ordi-(C₁-C₄)-alkylamino and phenyl and 5- or 6-membered heteroaryl fortheir part may be substituted up to two times by identical or differentsubstituents from the group consisting of fluorine, chlorine, cyano,(C₁-C₄)-alkyl, trifluoromethyl, (C₁-C₄)-alkoxy and trifluoromethoxy, andR⁶ represents hydrogen, fluorine or chlorine.
 3. The compound of theformula (I) as claimed in claim 1, in which A and E both represent CH, Zrepresents O, n represents the number 0 or 2, R¹ represents(C₁-C₄)-alkyl which may be substituted by hydroxyl, (C₁-C₄)-alkoxy,hydroxycarbonyl, aminocarbonyl, (C₃-C₆)-cycloalkyl, phenyl or 5-memberedheteroaryl or up to three times by fluorine, or represents(C₃-C₆)-cycloalkyl, phenyl or 5-membered heteroaryl, where the phenyland heteroaryl groups mentioned may be substituted up to two times byidentical or different substituents from the group consisting offluorine, chlorine, cyano, methyl, trifluoromethyl, methoxy andtrifluoromethoxy, R² represents hydrogen, R³ represents cyano, acetyl or(2-hydroxyethoxy)carbonyl, R⁴ represents methyl or R³ and R⁴ areattached to one another and together form a fused group of the formula

in which * denotes the point of attachment to the 5-position, shown informula (I), of the dihydropyrimidine ring and ** denotes the point ofattachment to the 6-position, shown in formula (I), of thedihydropyrimidine ring and R⁹ represents hydrogen, (C₁-C₄)-alkyl or(C₃-C₆)-cycloalkyl, where (C₁-C₄)-alkyl may be substituted by hydroxylor (C₁-C₄)-alkoxy, R⁵ represents hydrogen or (C₁-C₄)-alkyl which may besubstituted by cyano or di-(C₁-C₄)-alkylamino, or represents a group ofthe formula -L²-C(═O)—NR¹²R¹³, -L²-C(═O)—NH—NR¹²R¹³ or -L²-SO₂—R¹⁵, inwhich L² represents a bond, —CH₂—, —CH₂CH₂— or —CH(CH₃)—, R¹² representshydrogen or (C₁-C₄)-alkyl which may be substituted by hydroxyl or(C₁-C₄)-alkoxy, R¹³ represents hydrogen, (C₁-C₆)-alkyl or(C₃-C₆)-cycloalkyl, where (C₁-C₆)-alkyl may be substituted up to twotimes by identical or different substituents from the group consistingof hydroxyl, (C₁-C₄)-alkoxy, hydroxycarbonyl, (C₁-C₄)-alkoxycarbonyl andaminocarbonyl and in (C₁-C₆)-alkyl a CH₂ group may be replaced by anoxygen atom, if this results in a chemically stable compound, or R¹² andR¹³ together with the nitrogen atom to which they are attached form a 5-or 6-membered heterocycle which may contain a further ring heteroatomfrom the group consisting of N, O and S and may be substituted by(C₁-C₄)-alkyl, hydroxyl, (C₁-C₄)-alkoxy, oxo, hydroxycarbonyl,aminocarbonyl, 4- to 6-membered heterocyclyl or 5- or 6-memberedheteroaryl, where (C₁-C₄)-alkyl for its part may be substituted byhydroxyl, (C₁-C₄)-alkoxy or hydroxycarbonyl, and R¹⁵ represents(C₁-C₄)-alkyl, (C₃-C₆)-cycloalkyl or phenyl, where (C₁-C₄)-alkyl may besubstituted by (C₃-C₆)-cycloalkyl and phenyl may be substituted up totwo times by identical or different substituents from the groupconsisting of fluorine, chlorine, cyano, methyl, trifluoromethyl,methoxy and trifluoromethoxy, and R⁶ represents hydrogen or fluorine. 4.The compound of the formula (I) as claimed in claim 1, in which A and Eboth represent CH, Z represents O, n represents the number 0 or 2, R¹represents (C₁-C₄)-alkyl which may be substituted by hydroxyl,(C₁-C₄)-alkoxy, hydroxycarbonyl, aminocarbonyl, (C₃-C₆)-cycloalkyl orphenyl, or represents (C₃-C₆)-cycloalkyl or phenyl, where the phenylgroups mentioned may be substituted up to two times by identical ordifferent substituents from the group consisting of fluorine, chlorine,cyano, methyl, trifluoromethyl, methoxy and trifluoromethoxy, R²represents hydrogen, R³ represents cyano or acetyl, R⁴ represents methylor R³ and R⁴ are attached to one another and together form a fused groupof the formula

in which * denotes the point of attachment to the 5-position, shown informula (I), of the dihydropyrimidine ring and ** denotes the point ofattachment to the 6-position, shown in the formula (I), of thedihydropyrimidine ring and R⁹ represents hydrogen, (C₁-C₄)-alkyl or(C₃-C₆)-cycloalkyl, where (C₁-C₄)-alkyl may be substituted by hydroxylor (C₁-C₄)-alkoxy, R⁵ represents hydrogen, (C₁-C₄)-alkyl or a group ofthe formula -L²-C(═O)—NR¹²R¹³, -L²-C(═O)—NH—NR¹²R¹³ or -L²SO₂—R¹⁵, inwhich L² represents a bond, —CH₂—, —CH₂CH₂— or —CH(CH₃)—, R¹² representshydrogen or (C₁-C₄)-alkyl which may be substituted by hydroxyl or(C₁-C₄)-alkoxy, R¹³ represents hydrogen, (C₁-C₆)-alkyl or(C₃-C₆)-cycloalkyl, where (C₁-C₆)-alkyl may be substituted up to twotimes by identical or different substituents from the group consistingof hydroxyl, (C₁-C₄)-alkoxy, hydroxycarbonyl, (C₁-C₄)-alkoxycarbonyl andaminocarbonyl and in (C₁-C₆)-alkyl a CH₂ group may be replaced by anoxygen atom, if this results in a chemically stable compound, or R¹² andR¹³ together with the nitrogen atom to which they are attached form a 5-or 6-membered heterocycle which may contain a further ring heteroatomfrom the group consisting of N, O and S and may be substituted by(C₁-C₄)-alkyl, hydroxyl, (C₁-C₄)-alkoxy or oxo, where (C₁-C₄)-alkyl forits part may be substituted by hydroxyl or (C₁-C₄)-alkoxy, and R¹⁵represents (C₁-C₄)-alkyl, (C₃-C₆)-cycloalkyl or phenyl, where phenyl maybe substituted up to two times by identical or different substituentsfrom the group consisting of fluorine, chlorine, cyano, methyl,trifluoromethyl, methoxy and trifluoromethoxy, and R⁶ representshydrogen or fluorine.
 5. The compound of the formula (I) as claimed inclaim 1, in which A and E both represent CH, Z represents O, nrepresents the number 2, R¹ represents (C₁-C₄)-alkyl which may besubstituted by hydroxyl, (C₁-C₄)-alkoxy, cyclopropyl, cyclobutyl orphenyl or up to three times by fluorine, R² represents hydrogen, R³represents cyano or (2-hydroxyethoxy)carbonyl, R⁴ represents methyl, R⁵represents hydrogen, (C₁-C₄)-alkyl or a group of the formula-L²-C(═O)—NH—R¹³ or —SO₂—R¹⁵, in which L² represents a bond or —CH₂—,R¹³ represents hydrogen or (C₁-C₄)-alkyl which may be substituted byhydroxyl or (C₁-C₄)-alkoxy, or (C₃-C₆)-cycloalkyl and R¹⁵ represents(C₁-C₄)-alkyl or (C₃-C₆)-cycloalkyl, and R⁶ represents hydrogen.
 6. Thecompound of the formula (I) as claimed in claim 1, in which A and E bothrepresent CH, Z represents O, n represents the number 2, R¹ represents(C₁-C₄)-alkyl which may be substituted by hydroxyl or (C₁-C₄)-alkoxy, R²represents hydrogen, R³ represents cyano, R⁴ represents methyl, R⁵represents hydrogen, (C₁-C₄)-alkyl or a group of the formula—CH₂—C(═O)—NH—R¹³ or —SO₂—R¹⁵, in which R¹³ represents hydrogen or(C₁-C₄)-alkyl which may be substituted by hydroxyl or (C₁-C₄)-alkoxy andR¹⁵ represents (C₁-C₄)-alkyl or (C₃-C₆)-cycloalkyl, and R⁶ representshydrogen.
 7. A process for preparing a compound of the formula (I) asdefined in claim 1, characterized in that a compound of the formula (II)

in which A, E, n, R¹ and R² have the meanings given in claim 1, isreacted in the presence of an acid or an acid anhydride in a 3-componentone-pot reaction or sequentially with a compound of the formula (III)

in which R³ and R⁴ have the meanings given in claim 1, and a compound ofthe formula (IV)

in which Z and R⁶ have the meanings given in claim 1, to give a compoundof the formula (I-A)

in which A, E, Z, n, R¹, R², R³, R⁴ and R⁶ each have the meanings givenin this claim, and this compound is, in the case that R⁵ in formula (I)does not represent hydrogen, reacted in the presence of a base with acompound of the formula (V)R^(5A)—X  (V), in which R^(5A) has the meaning of R⁵ given in claim 1,but does not represent hydrogen, and X represents a leaving group, suchas, for example, halogen, mesylate, tosylate or triflate, to give acompound of the formula (I-B)

in which A, E, Z, n, R¹, R², R³, R⁴, R^(5A) and R⁶ each have themeanings given above, and the compound of the formula (I-A) or (I-B)obtained in this manner is, if appropriate, separated by methods knownto the person skilled in the art into its enantiomers and/ordiastereomers and/or converted with the appropriate (i) solvents and/or(ii) bases or acids into its salts. 8-10. (canceled)
 11. A medicamentcomprising a compound as defined in claim 1 in combination with one ormore inert non-toxic pharmaceutically acceptable auxiliaries.
 12. Amedicament comprising a compound as defined in claim 1 in combinationwith one or more further active compounds selected from the group of thekinase inhibitors, the matrix metalloprotease inhibitors, stimulatorsand activators of soluble guanylate cyclase, prostacyclin analogs,endothelin receptor antagonists, phosphodiesterase inhibitors,beta-adrenergic receptor agonists, anticholinergics and glucocorticoids.13. (canceled)
 14. A method for the treatment and/or prevention ofpulmonary arterial hypertension (PAH) and other forms of pulmonaryhypertension (PH), or chronic-obstructive pulmonary diseases (COPD), ofacute lung injury (ALI), of acute respiratory distress syndrome (ARDS),of pulmonary emphysema, of alpha-1 antitrypsin deficiency (AATD) and ofcystic fibrosis (CF) in humans and animals using an effective amount ofat least one compound as defined in claim 1.